Autophagy inhibition enhances therapy-induced = apoptosis in a Myc-induced model of lymphoma

Journal=20 List > J=20 Clin Invest > v.1= 17(2);=20 Feb 1, 2007

PubMed articles by:

J Clin Invest. = 2007 February 1; = 117(2):=20 326=E2=80=93336.

Published online 2007 = January 18.=20 doi: = 10.1172/JCI28833.

PMCID:=20 PMC1765515

Autophagy inhibition enhances = therapy-induced=20 apoptosis in a Myc-induced model of lymphoma

Ravi K.=20 Amaravadi,^1,² Duonan Yu,³ Julian = J.=20 Lum,² Thi Bui,² Maria A. = Christophorou,⁴=20 Gerard I. Evan,⁴ Andrei Thomas-Tikhonenko,³ = and=20 Craig B. Thompson^1,²

¹Division of Hematology/Oncology, = Department=20 of Medicine, ²Department of Cancer Biology, Abramson = Family=20 Cancer Research Institute, and ³Department of = Pathobiology,=20 University of Pennsylvania, Philadelphia, Pennsylvania, USA.=20 ⁴Cancer Research Institute, University of California = San=20 Francisco Comprehensive Cancer Center, San Francisco, California, = USA.=20

Address correspondence to: Craig B. = Thompson,=20 Department of Cancer Biology, Abramson Family Cancer Research = Institute,=20 421 Curie Boulevard, 450 BRB II/III, Philadelphia, Pennsylvania = 19104,=20 USA. Phone: (215) 746-5515; Fax: (215) 746-5511; E-mail: craig/at/mail.med.upenn.edu .

Received April 17, 2006; Accepted November = 28,=20 2006.

=20 This article has been cited=20 by other articles in PMC.

Supplementary=20 Material

References

Abstract

Autophagy is a=20 lysosome-dependent degradative pathway frequently activated in = tumor cells=20 treated with chemotherapy or radiation. Whether autophagy observed = in=20 treated cancer cells represents a mechanism that allows tumor = cells to=20 survive therapy or a mechanism for initiating a nonapoptotic form = of=20 programmed cell death remains controversial. To address this = issue, the=20 role of autophagy in a Myc-induced model of lymphoma = generated=20 from cells derived from=20 p53ER^TAM/p53ER^TAM = mice=20 (with ER denoting estrogen receptor) was = examined. Such=20 tumors are resistant to apoptosis due to a lack of nuclear p53. = Systemic=20 administration of tamoxifen led to p53 activation and tumor = regression=20 followed by tumor recurrence. Activation of p53 was associated = with the=20 rapid appearance of apoptotic cells and the induction of autophagy = in=20 surviving cells. Inhibition of autophagy with either chloroquine = or=20 ATG5 short hairpin RNA (shRNA) enhanced the ability of = either p53=20 activation or alkylating drug therapy to induce tumor cell death. = These=20 studies provide evidence that autophagy serves as a survival = pathway in=20 tumor cells treated with apoptosis activators and a rationale for = the use=20 of autophagy inhibitors such as chloroquine in combination with = therapies=20 designed to induce apoptosis in human cancers.

Supplementary=20 Material

References

Introduction

Macroautophagy (referred to hereafter as autophagy) is a = process=20 conserved by evolution that allows cells to sequester cytoplasmic = contents=20 through the formation of double-membrane vesicles (autophagosomes) = and=20 target them for degradation through the fusion of autophagosomes = with=20 lysosomes, creating single-membrane autolysosomes. A number of=20 antineoplastic therapies have been observed to induce autophagy in = human=20 cancer cell lines (1=E2=80=934).=20 Whether autophagy induced by therapy contributes to tumor cell = death or=20 represents a mechanism of resistance to therapy-mediated cell = death=20 remains uncertain. Two observations that argue in favor of = autophagy as a=20 reflection of the therapeutic efficacy of antineoplastic agents = are (a)=20 that persistent activation of autophagy can lead to programmed = cell death=20 (5)=20 and (b) that the autophagy regulator beclin 1 (BECN1) is = a=20 haploinsufficient tumor-suppressor gene that induces autophagy = when=20 overexpressed (6).=20 These findings suggest that stimulation of autophagy may be = detrimental to=20 cancer cells and that therapies that inhibit autophagy may lead to = enhanced tumor growth.

Accumulating evidence suggests that autophagy can also = represent an=20 adaptive strategy by which cells clear damaged organelles and = survive=20 bioenergetic stress. Autophagy, by targeting cytoplasmic proteins = and=20 organelles for lysosomal degradation, plays a role in recycling = organelles=20 and proteins that may be damaged by increased reactive oxygen = species=20 generated by the cellular stress associated with activated = oncogenes and=20 cancer therapies (7,=20 8).=20 Autophagy also promotes the survival of cells resistant to = apoptosis when=20 they are deprived of extracellular nutrients or growth factors. = Treatment=20 of such cells dependent on autophagy for survival with the drug=20 chloroquine (CQ) results in brisk cell death (9).=20

CQ is a lysosomotropic drug that raises intralysosomal pH (10)=20 and impairs autophagic protein degradation (11).=20 By blocking the last step of the autophagy pathway, either CQ = treatment=20 (9)=20 or knockdown of the lysosomal protein LAMP-2 (12)=20 leads to the accumulation of ineffective autophagosomes and cell = death in=20 cells reliant on autophagy for survival. Due to its favorable = therapeutic=20 index in animals, CQ could be used as a tool to investigate the = role of=20 autophagy as a response to therapeutic stress in tumors grown in = mice.=20

To test the effect of CQ and its modulation of tumor cell = autophagy in=20 vivo, a mouse model of B cell lymphoma was generated. This model = utilizes=20 a p53=E2=80=93estrogen receptor knockin mouse=20 (p53ER^TAM/p53ER^TAM) that allows for = the in=20 vivo temporal dissection of the effects of p53 activation (13).=20 Bone marrow cells from these mice were infected in vivo with a=20 Myc-expressing retrovirus at high multiplicity in the flanks of = recipient=20 mice. This reproducibly gave rise to polyclonal=20 Myc/p53ER^TAM lymphomas with a B cell = phenotype. These=20 tumors can be utilized in therapeutic studies because of their = ability to=20 be adoptively transferred to the flanks of syngeneic mice. In the = absence=20 of therapy, the resulting tumors grow rapidly, as they are = effectively=20 Myc positive, p53 null. Upon systemic = administration of=20 tamoxifen (TAM), the p53ER fusion protein translocates to the = nucleus,=20 restoring p53 function and initiating apoptosis and tumor = regression.=20 After a period of tumor latency, 100% of animals experience tumor=20 recurrence despite continuous TAM treatment.

In the present study, CQ significantly enhanced tumor = regression and=20 delayed tumor recurrence following activation of p53 or = administration of=20 cytotoxic chemotherapy. Autophagy was activated in tumor cells = that=20 survived apoptosis following therapeutic stress. CQ treatment at = low=20 micromolar doses inhibited autophagy-dependent survival of tumor = cells,=20 and its effects were similar to that of the genetic knockdown of = the=20 essential autophagy gene ATG5 in enhancing p53-induced = apoptotic=20 cell death. Combining CQ at these doses with short hairpin RNA = (shRNA)=20 against ATG5 did not further enhance cell death following = p53=20 activation. This study provides evidence that tumor cells can = survive=20 therapy-induced apoptosis through the process of autophagy and = provides=20 the rationale for further investigations of autophagy inhibitors = as=20 potentiators of anticancer agents.

Supplementary=20 Material

References

Results

Tumor regression induced by p53 = is=20 enhanced by CQ.

The p53ER^TAM fusion gene = consists=20 of a transcriptionally inactive hormone-binding region of the ER=20 (ER^TAM) (14)=20 fused to the entire coding region of the Trp53 tumor = suppressor=20 gene (15).=20 In mice homozygous for knockin alleles encoding = p53ER^TAM=20 (Trp53^KI/KI), p53-dependent gene expression is = induced=20 by systemic administration of TAM (13).=20 To generate B cell lymphomas, bone marrow cells were harvested = from=20 Trp53^KI/KI mice and were transduced in vivo = with the=20 LMycSN retrovirus as previously described (16,=20 17).=20

To examine the in vivo antitumor effect of CQ treatment in the = absence=20 of p53 activation, tumor cells were harvested from a=20 Myc/p53ER^TAM lymphoma and were injected = subcutaneously=20 into the flanks of syngeneic mice. After tumor formation, mice = were=20 matched for tumor volumes and randomly assigned to receive PBS or = 60=20 mg/kg/d CQ i.p. (Figure 1A).=20 This dose is near the previously reported LD₅₀ of = 68=E2=80=9378 mg/kg=20 (18).=20 Mice treated at these doses had no observed toxicity. Treatment = with 60=20 mg/kg/d CQ i.p. resulted in a modest but reproducible impairment = in the=20 rate of tumor growth compared with that in PBS controls. However, = tumor=20 regression was not observed in any of the CQ-treated animals. = Daily=20 treatment with the CQ derivative hydroxychloroquine (HCQ) at 60 = mg/kg/d=20 resulted in similar impairment in tumor growth (data not shown). =

Figure=20 1

Effects = of CQ with=20 and without p53 activation on the regression of=20 Myc/p53ER^TAM lymphomas.=20

To determine the effect of CQ treatment after therapeutic = activation of=20 apoptosis, Myc/p53ER^TAM lymphomas were = generated and=20 mice were matched for tumor volume and randomly assigned to = receive either=20 daily TAM plus PBS i.p. (TAM/PBS) or daily TAM plus 60 mg/kg/d CQ = i.p.=20 (TAM/CQ). TAM treatment led to nuclear localization of the=20 p53ER^TAM fusion protein and the rapid induction of = apoptosis=20 (data not shown). TAM/PBS-treated tumors regressed over several = days, but=20 all tumors resumed growth despite continued TAM therapy. TAM/CQ = treatment=20 resulted in a significant delay in tumor recurrence in comparison = with=20 TAM/PBS treatment (Figure 1B).=20 In separate experiments, 60 mg/kg/d HCQ i.p. also resulted in=20 significantly delayed recurrence (data not shown). In all mice = treated=20 over the course of 4 separate experiments, complete clinical = regression of=20 tumor in response to therapy was observed in 81% of mice treated = with=20 TAM/CQ or TAM/HCQ compared with 8% of mice treated with TAM/PBS=20 (P < 0.005).

Autophagy is activated in tumor = cells=20 that survive p53-dependent apoptosis.

The activation of = autophagy=20 following oncogenic or chemotherapeutic stress has been observed = in=20 multiple cancer cell lines (11,=20 14).=20 To further understand the effects of CQ and/or p53 activation on = tumor=20 cell autophagy in this tumor model, electron microscopy was = performed on=20 lymphoma tissue obtained from mice treated with either PBS or 60 = mg/kg/d=20 CQ i.p. in the absence of p53 activation and from mice treated = with either=20 TAM/PBS or TAM/CQ at sequential time points after p53 activation. = While=20 cells that contained rare autophagosomes were found in PBS-treated = tumors,=20 tumor cells with multiple autophagosomes were easily visualized in = Myc/p53ER^TAM tumors treated with CQ for 96 = hours in=20 the absence of p53 activation (Figure 2A).=20 CQ disrupts lysosomal structure and function (19),=20 preventing effective autophagic degradation, leading to the = accumulation=20 of ineffective autophagosomes (11,=20 20,=20 21).=20 Eight hours after the first administration of TAM, p53 activation = induced=20 morphological changes characteristic of apoptosis in the majority = of tumor=20 cells, including chromatin condensation, nuclear and cytoplasmic = blebbing,=20 and nuclear fragmentation. By focusing on cells with intact = nuclear=20 morphology and cytoplasmic membranes, numerous tumor cells were = identified=20 in tumors from both treatment groups that had survived p53-induced = apoptosis. In nonapoptotic cells, TAM/PBS treatment resulted in = the=20 appearance of large double-membrane vesicles by 24 hours and 48 = hours. By=20 48 hours, most tumor cells had smaller residual autophagosomes as = tumors=20 began to recur. In contrast, viable tumor cells in TAM/CQ-treated = tumors=20 accumulated autophagosomes at 8 hours following p53 activation, = and by 24=20 hours, viable tumor cells were fewer in number and contained = numerous=20 ineffective autophagosomes with undegraded or partially degraded = contents.=20 By 48 hours, TAM/CQ-treated tumors consisted largely of the = remains of=20 apoptotic cells.=20

Figure=20 2

Effects = of p53=20 activation with and without CQ on autophagosome=20 = accumulation.

Quantification of the number of autophagosomes per nonapoptotic = cell=20 (Figure 2B)=20 demonstrated that p53 activation alone (TAM/PBS) resulted in an = 8-fold=20 increase in the number of autophagosomes compared with tumors = treated with=20 PBS alone by 24 hours after the initiation of TAM treatment. The=20 appearance of numerous autophagosomes occurred earlier in = TAM/CQ-treated=20 tumors. Both in the absence of p53 activation and at each time = point=20 following p53 activation, CQ treatment resulted in a significant = increase=20 in the number of autophagosomes per nonapoptotic cell.

CQ treatment enhances = p53-induced=20 apoptosis.

Low magnification (=C3=974,000) electron = micrographs of tumors=20 treated with PBS alone compared with tumors treated with TAM/PBS = or TAM/CQ=20 at 48 hours after the initiation of TAM treatment demonstrated = widespread=20 cell death in TAM/CQ-treated tumors (Figure 3A).=20 Morphological characteristics of apoptosis were observed in = electron=20 micrographs in 92% =C2=B1 5% of tumor cells in TAM/CQ-treated = tumors compared=20 with 3% =C2=B1 3% of tumor cells in TAM/PBS-treated tumors (Figure = 3B).=20 To further characterize this cell death, TUNEL staining was = performed on=20 tumor specimens to assess the number of cells undergoing apoptosis = in=20 treated tumors (Figure 3C).=20 At 8 hours after the initiation of treatment, both TAM/PBS and = TAM/CQ=20 treatments resulted in a marked increase in TUNEL-positive tumor = cells=20 compared with PBS- and CQ-treated tumors. The number of = TUNEL-positive=20 cells decreased by 48 hours in TAM/PBS-treated but not in = TAM/CQ-treated=20 tumors. Quantification of the percentage of TUNEL-positive cells = per=20 high-powered field in treated tumors (Figure 3C)=20 found no significant differences in the percentage of = TUNEL-positive cells=20 between PBS- and CQ-treated tumors and between TAM/PBS and = TAM/CQ-treated=20 tumors at 8 hours. At 24 hours, a significantly greater percentage = of=20 TUNEL-positive tumor cells was observed in TAM/CQ-treated tumors = in=20 comparison with TAM/PBS-treated tumors. This difference persisted = at 48=20 hours, when a 7-fold difference in the percentage of = TUNEL-positive tumor=20 cells was observed in TAM/CQ-treated tumors compared with = TAM/PBS-treated=20 tumors (P < 0.001). As an independent measure of tumor = cell=20 apoptosis in treated tumors, Western blot analysis of cleaved = caspase-3=20 was performed on tumor cell lysates from TAM/PBS- and = TAM/CQ-treated=20 tumors. Increased cleaved caspase-3 was observed in tumor lysates = obtained=20 at 8 hours after the initiation of either TAM/PBS or TAM/CQ. = Cleaved=20 caspase-3 was absent in TAM/PBS-treated tumor cell lysates = obtained at 48=20 hours but present in TAM/CQ-treated tumor lysates obtained at 48 = hours=20 (data not shown).=20

Figure=20 3

Effects = of p53=20 activation with and without CQ on=20 apoptosis.

CQ enhances p53-dependent = apoptosis by=20 inhibiting autophagy.

To ensure that the changes in = autophagosome=20 number seen by electron microscopy were due to the direct action = of the=20 systemically administered drugs on the autophagy pathway in tumor = cells=20 and not to changes in tumor microenvironment induced by tumor = degeneration=20 following treatment, the GFP-LC3 (LC3, mammalian homolog of yeast = Atg8)=20 fusion gene was retrovirally transduced into a bulk population of = cells=20 harvested from a primary Myc/p53ER^TAM = lymphoma, and=20 GFP-positive cells were passaged in culture. LC3 is processed from = LC3-I=20 to LC3-II during autophagy. LC3-II is inserted into newly formed=20 autophagosome membranes (22).=20 Expression of GFP-LC3 provides a means to track changes in = autophagosome=20 formation in living cells (23).=20 The distribution of GFP-LC3 in untreated=20 Myc/p53ER^TAM/GFP-LC3 cells was diffusely = cytoplasmic=20 (Figure 4A).=20 CQ=E2=80=99s ability to modulate autophagy in tumor cells was = confirmed by the=20 accumulation of LC3-positive vesicles following treatment of=20 Myc/p53ER^TAM/GFP-LC3 cells with CQ. Activation = of p53=20 with 4-hydroxytamoxifen (hTAM) resulted in an increased number of = punctate=20 LC3-associated vesicles, which was further enhanced by combined = treatment=20 with hTAM and CQ. The accumulation of autophagosomes in CQ-treated = cells=20 was dose dependent in both the absence and presence of hTAM = (Figure 4B).=20 In the absence of hTAM, CQ doses between 500 nM and 5 =CE=BCM = resulted in a=20 2-fold to 10-fold increase in the percentage of cells with = punctate=20 GFP-LC3 fluorescence. Treatment with hTAM alone resulted in a = 10-fold=20 increase in the percentage of cells with punctate GFP-LC3 = fluorescence.=20 The addition of CQ (1=E2=80=935 =CE=BCM) during treatment with = hTAM resulted in a=20 dose-dependent increase in the percentage of cells with punctate = GFP-LC3=20 fluorescence. These differences persisted without significant = change when=20 measured at 48 hours after treatment (data not shown). To ensure = that CQ=E2=80=99s=20 ability to modulate autophagy was independent of p53,=20 p53^+/+ GFP-LC3 and = p53^{=E2=80=93/=E2=80=93}GFP-LC3=20 mouse embryonic fibroblasts (MEFs) were generated. CQ induced the=20 accumulation of punctate LC3-associated vesicles in MEFs in a=20 p53-independent manner (Figure 4C).=20 Treatment of p53^+/+GFP-LC3 MEFs with hTAM did = not=20 result in punctate LC3 fluorescence (data not shown). This result=20 confirmed that the punctate LC3 fluorescence observed in=20 Myc/p53ER^TAM lymphoma cells treated with hTAM = was due=20 to hTAM-induced activation of the p53ER^TAM fusion = protein.=20 Since the ER^TAM protein domain is a transcriptionally=20 inactivated ER, punctate GFP-LC3 fluorescence in hTAM-treated=20 Myc/p53ER^TAM cells is a p53-mediated effect.=20

Figure=20 4

Effects = of p53=20 activation with and without CQ on LC3=20 = relocalization.

To confirm that the antineoplastic effect of CQ observed in = vivo=20 results from the ability of CQ to inhibit autophagy-based = survival, CQ=20 treatment of tumor cells was compared with the genetic inhibition = of=20 autophagy using shRNA against the autophagy gene ATG5 = (shATG5).=20 Expression of shATG5 blocks autophagy at a proximal step by = preventing the=20 formation of the ATG5-ATG12 complex, which is required for the = generation=20 of autophagosomes (24).=20 shRNA designed to silence no mouse or human genes (hairpin = control, HC)=20 and 2 distinct shRNA sequences against ATG5 (shATG5 = hairpin 2=20 [h2], shATG5 hairpin [h7]) were cloned into the control expression = vector=20 pKD (9)=20 and introduced into primary tumor cells harvested from a=20 Myc/p53ER^TAM B cell lymphoma. Decreased = expression=20 levels of the ATG5-ATG12 complex in cells expressing shATG5 h2=20 (h2) and shATG5 h7 (h7) but not in cells = expressing HC=20 (HC) or vector (V) was confirmed by Western blot = (Figure=20 5A).=20 Tumor cells were induced to undergo apoptosis when p53 was = activated by=20 hTAM treatment in vitro. p53 activation with hTAM in h2 = and=20 h7 cells in which ATG5 levels were chronically suppressed = resulted in increased cell death compared with HC cells = (Figure=20 5B).=20 Autophagy has been reported to promote cell survival in response = to stress=20 through both its ability to clear damaged organelles (25)=20 and its ability to recycle intracellular contents to maintain=20 bioenergetics (26).=20 To determine whether the proapoptotic effect of chronic autophagy=20 suppression could be reversed by supplying a permeable nutrient to = support=20 bioenergetics, cells were treated with hTAM and methyl pyruvate. = Methyl=20 pyruvate is a cell-permeant intermediate of glucose metabolism = that has=20 been previously reported to maintain the viability of growth = factor=E2=80=93=20 and/or nutrient-depleted cells in which autophagy is impaired (9).=20 Methyl pyruvate addition to the medium failed to rescue the = enhanced cell=20 death observed in h2 cells as well as h7 cells = following=20 p53 activation with hTAM (Figure 5C).=20

Figure=20 5

Effects = of p53=20 activation with and without knockdown of ATG5 on tumor cell=20 death.

The effect of CQ treatment on tumor cell death following p53 = activation=20 with hTAM was examined in cells stably transfected with HC or 1 of = 2=20 distinct shATG5-expressing vectors (h2, h7; = Figure 5A).=20 CQ treatment (1=E2=80=935 =CE=BCM) of HC cells enhanced = tumor cell death in=20 response to p53 induction in a dose-dependent fashion (Figure 6A).=20 In this dose range, CQ alone had no reproducible effect on tumor = cell=20 viability or proliferation (Supplemental Figure 1; available = online with=20 this article; doi:10.1172/JCI28833DS1). In contrast, CQ treatment = failed=20 to enhance the cell death of either clone of shATG5-transfected = cells at=20 these doses (Figure 6,=20 B and C).

Figure=20 6

Effects = of CQ or=20 ATG5 knockdown in combination with p53 activation on tumor = cell=20 death.

CQ enhances tumor regression = and=20 suppresses tumor recurrence after alkylating drug therapy.

In = the=20 treatment of human lymphomas, alkylating agents such as = cyclophosphamide=20 serve as first-line therapies (27=E2=80=9329).=20 To determine whether the inhibition of autophagy could enhance the = efficacy of alkylating drug therapy in tumors resistant to = apoptosis, mice=20 bearing Myc/p53ER^TAMlymphomas were treated = with=20 cyclophosphamide alone or in combination with CQ. Mice with=20 Myc/p53ER^TAMlymphomas were treated with a = single dose=20 of 50 mg/kg cyclophosphamide i.p. followed by treatment with = either PBS or=20 60 mg/kg/d CQ i.p. The PBS or CQ treatment was then repeated daily = for 13=20 days (Figure 7A).=20 Cyclophosphamide with or without CQ led to complete tumor = regression in=20 all treated mice. CQ cotreatment significantly enhanced tumor = regression=20 and delayed tumor recurrence. The average tumor volume after 24 = hours of=20 treatment in cyclophosphamide/PBS-treated and = cyclophosphamide/CQ-treated=20 animals was 2,966 =C2=B1 673 mm³, and 1,489 =C2=B1 524 = mm³,=20 respectively (P < 0.001). The addition of CQ to=20 cyclophosphamide more than doubled the average time to recurrence = of=20 tumors. The tumors of PBS-treated mice (Figure 5)=20 recurred after an average of 4.1 =C2=B1 1.2 days whereas a limited = course of CQ=20 treatment delayed tumor recurrence to an average of 9.3 =C2=B1 3.5 = days=20 (P < 0.01) (Figure 7B).=20

Figure=20 7

Effects = of=20 alkylating chemotherapy with and without CQ in=20 Myc/p53ER^TAMlymphomas.=20

To investigate the effects of alkylating chemotherapy on = autophagy,=20 Myc/p53ER^TAMcells expressing GFP-LC3 = were=20 treated with the alkylating agent = N-methyl-N=E2=80=B2-nitro-N-nitrosoguanidine=20 (MNNG) with and without CQ (Figure 7C).=20 MNNG is an alkylating agent that can induce apoptosis in a = p53-independent=20 manner (30).=20 CQ treatment or MNNG treatment alone resulted in an increased = percentage=20 of viable cells with punctate LC3 fluorescence, indicating an = accumulation=20 of autophagosomes. Combination treatment with MNNG and CQ resulted = in=20 9-fold and 17-fold increases in punctate LC3 fluorescence compared = with=20 DMSO control at 24- and 48-hour time points (Figure 7D).=20 To further compare the effect of genetic autophagy inhibition with = that of=20 CQ following cytotoxic therapy, the effect of MNNG treatment with = and=20 without CQ was tested in HC, h2, and h7 = cells.=20 At 24 and 48 hours, combined treatment with 5 =CE=BCM CQ = significantly enhanced=20 the cytotoxic effect of MNNG treatment of HC lymphoma = cells to a=20 degree similar to that of treatment of h2 or h7 = cells=20 with MNNG alone. CQ treatment did not further enhance cell death = induced=20 by an alkylating agent in h2 or h7 cells (Figure = 7E).=20

Supplementary=20 Material

References

Discussion

The results described in this study provide evidence that = autophagy can=20 be an adaptive mechanism that contributes to tumor cell survival = and=20 resistance to therapy-induced apoptosis. Induction of p53 in=20 Mycp53ER^TAMtumors results in the induction of = tumor=20 cell apoptosis, and tumor cells that survive the acute induction = of=20 p53-induced apoptosis display active autophagy. Impairment of = autophagic=20 vesicle clearance by the lysosomotropic drug CQ correlated with = enhanced=20 apoptosis and tumor regression as well as delayed tumor = recurrence. This=20 appears to be due to a direct prosurvival effect of autophagy in = tumor=20 cells, since autophagy inhibition by either ATG5 shRNA or = CQ=20 enhances tumor cell apoptosis and suppresses tumor cell recovery = when p53=20 is induced in vitro.

CQ has the ability to disrupt lysosomal function (10),=20 inhibiting the last critical step in autophagy, the acid-dependent = degradation of autophagosome contents, which results in the = accumulation=20 of autophagic vesicles that cannot be cleared (11).=20 Although CQ at higher doses may have additional detrimental = effects (31,=20 32)=20 on tumor cell viability, the CQ doses studied here failed to cause = tumor=20 regression in vivo or induce the death of tumor cells in vitro. = The=20 ability of CQ to augment tumor cell death in response to p53 = activation or=20 alkylating drug therapy correlated with its ability to impair = autophagy. A=20 similar augmentation of tumor cell death in response to p53 = activation or=20 alkylating drug therapy was observed in cells in which autophagy = is=20 genetically suppressed by shATG5. CQ treatment failed to further = augment=20 cell death in cells lacking functional autophagy following p53 = activation=20 or alkylating drug therapy. Thus, at the doses studied here, = inhibition of=20 autophagy is likely the basis of CQ=E2=80=99s major antineoplastic = effect.=20 Together, these data demonstrate that inhibitors of autophagy = enhance the=20 efficacy of therapeutic strategies designed to induce tumor cell=20 apoptosis.

Prior studies have led to conflicting views of the role of = autophagy in=20 tumor cell biology. Suppression or deficiency of autophagy genes = has been=20 shown to enhance tumorigenesis (6),=20 leading to the conclusion that rapidly growing tumors downregulate = autophagy. Consistent with this finding, the autophagy-associated = tumor=20 suppressor gene BECN1 is monoallelically deleted in many = breast=20 cancers, leading to reduced autophagy in the tumor cells (33,=20 34).=20 These observations suggest that autophagy may suppress tumor cell=20 outgrowth and raise the possibility that pharmacologic suppression = of=20 autophagy might enhance tumor cell growth and survival. In = contrast,=20 recent work has suggested that autophagy plays an important role = in=20 mammalian cell biology by providing cells an adaptive mechanism to = survive=20 bioenergetic stress as a result of either growth factor or = nutrient=20 deprivation (9).=20 A similar tumor-protective role for autophagy was identified by = other=20 investigators using an Akt-driven xenograft model defective in = apoptosis.=20 In this model, autophagy was activated in tumor cells at the = center of=20 growing tumors and served to protect tumor cells from necrosis = induced by=20 the combination of an activated oncogene and nutrient-limited = conditions=20 typically encountered by tumor cells in vivo. Interestingly, to = date no=20 tumors have been reported in which biallelic inactivation of=20 BECN1 or another autophagy gene has been observed, = suggesting=20 that the preservation of autophagy as an inducible survival = mechanism is=20 required for tumorigenesis. Selection for monoallelic loss of = autophagy=20 genes during tumorigenesis may be related to the reported function = of=20 autophagy in eliminating damaged or excess organelles (35,=20 36).=20 Yeast defective in UTH1, which encodes a mitochondrial = protein=20 required for effective targeting of mitochondria for autophagic=20 degradation (37),=20 are hypersensitive to certain types of oxidant injury (38).=20 Therefore, chronic suppression of autophagy over a long period of = time=20 would result in the accumulation of cellular oxidants that damage = DNA,=20 increasing the likelihood of cellular transformation. The role of=20 autophagy in suppressing the accumulation of oxidative damage to = cells may=20 account for autophagy=E2=80=99s role in suppressing tumorigenesis = while serving a=20 tumor-protective effect against various types of cellular stress=20 encountered by established tumors.

The present studies were undertaken because of numerous reports = of=20 autophagy observed in established cancer cell lines following = anticancer=20 therapy (1=E2=80=933,=20 39).=20 The data presented above demonstrate the induction of autophagy in = tumor=20 cells in vivo in response to the activation of p53, a gene = commonly=20 induced by a number of antineoplastic therapies. It has been = suggested=20 that the ability of radiation or chemotherapy to induce cell death = in=20 cancer cell lines that display resistance to apoptosis depends on = type II=20 programmed cell death executed by autophagy (40).=20 In Myc-induced lymphoma cells, knockdown of ATG5, an = essential=20 autophagy gene, did not impair p53-induced cell death, suggesting = that the=20 autophagy program that is activated with apoptosis does not = contribute to=20 cell death. Instead, autophagy is serving a survival function in = this=20 context since expression of shRNA directed against ATG5 = in=20 lymphoma cells augmented cell death following p53 activation. = These data=20 indicate that autophagy can be an adaptive response that allows = cancer=20 cells to survive an apoptotic stimulus that would otherwise lead = to their=20 demise.

The ability of tumor cells expressing ATG5 shRNA to = grow=20 suggests that once neoplastic proliferation is established, = autophagy is=20 not absolutely required for in vitro cell growth and survival. = However,=20 our data suggest that there is ongoing autophagy during=20 Myc/p53ER^TAM tumor growth, based on the = accumulation=20 of autophagic vesicles when their clearance by lysosomes is = inhibited by=20 CQ. When tumor cells are faced with cellular stress that induces=20 apoptosis, autophagy serves to protect against cell death. = Inhibition of=20 autophagy in the setting of an apoptotic stress enhances = apoptosis. Since=20 autophagy contributes to cell survival in times of stress, it = seems likely=20 it can provide enhanced survival to tumor cells subjected to = potentially=20 catastrophic stress even when expressed in a haploinsufficient = manner.=20

The tumors and tumor cells used in this study to investigate = the role=20 of autophagy following apoptotic stress were created by expressing = wild-type human c-Myc in mouse bone marrow cells from the = p53ER-knockin mouse. In addition to Burkitt lymphoma, in which a=20 chromosomal translocation juxtaposes the c-Myc gene to 1 = of 3=20 immunoglobulin genes, leading to its constitutive expression in B = cells=20 (41),=20 dysregulation of c-Myc through gene amplification (42=E2=80=9344),=20 c-Myc point mutations (45),=20 or constitutive transcriptional and posttranslational activation = (46,=20 47)=20 has been implicated in the pathogenesis of multiple malignancies,=20 including lung cancer, colon cancer, and breast cancer. The role = of Myc as=20 a transcriptional regulator of genes that affect glucose = metabolism and=20 its propensity to induce apoptosis (48)=20 when expressed acutely in nontransformed cells raises the = possibility that=20 autophagy observed in these tumors may be a specific consequence = of=20 introducing a therapeutic stress on top of Myc-induced = cellular=20 stress. Recently, however, autophagy was found to promote tumor = survival=20 in another tumor model driven by the oncogene Akt (49).=20 Akt, when activated, also increases glycolytic metabolism and = controls=20 apoptosis. In these tumors, autophagy is activated and = preferentially=20 protects tumor cells in the centers of growing = Akt-driven,=20 apoptosis-deficient tumors, where nutrients and oxygen are = limited. This=20 suggests that oncogenes that activate the Warburg effect, such as = Akt, and=20 drive the glycolytic phenotype frequently seen in a variety of = tumors may=20 predispose tumor cells to increase autophagy as a strategy for = survival in=20 the face of nutrient limitation. However, in=20 Myc/p53ER^TAM cells, the permeable nutrient = methyl=20 pyruvate did not rescue the enhanced p53-induced apoptosis = observed in=20 tumor cells in which autophagy was genetically silenced. Autophagy = can=20 promote cell survival not only by recycling cellular constituents = to=20 support bioenergetics but also by clearing damaged organelles, = whose=20 accumulation following cellular stress can further damage cells. = Autophagy=20 induced in response to p53-induced stress and cytotoxic = chemotherapy may=20 provide the tumor cell a means of clearing damaged organelles. = Together=20 with evidence of the role of autophagy as a tumor survival pathway = in=20 Akt-driven tumors, the data presented in this study of=20 Myc-driven lymphomas suggest that autophagy may serve as = a=20 generalized survival function in oncogene-transformed cells. = Further=20 investigation is required to fully understand the contribution of = other=20 oncogenes and tumor suppressor genes in determining the outcome of = combined autophagy inhibition and apoptosis induction. = Nevertheless, many=20 of the existing and experimental chemotherapeutic approaches for = the=20 treatment of cancer seek to induce tumor cell apoptosis. The data=20 presented here demonstrate that autophagy in response to either = p53=20 activation or alkylating drug therapy can contribute to the tumor = cell=E2=80=99s=20 ability to resist apoptosis. These studies identify CQ and the = related=20 compound HCQ as inhibitors of autophagy that can be used in vivo. =

The current data suggest that CQ may be an important adjunct to = enhance=20 the efficacy of existing chemotherapeutic strategies without = potentiating=20 toxicity. CQ cotreatment with TAM or with the alkylating agent=20 cyclophosphamide did not result in additional toxicity in the = treated=20 animals. This is consistent with the fact that CQ has been used = safely for=20 decades in patients for malaria prophylaxis (50)=20 and for the treatment of rheumatoid arthritis, where it is often = used in=20 combination with methotrexate (51).=20 The chemical structure of CQ derivatives allows them to serve as = weak=20 bases that become trapped in acidic compartments. Since glycolytic = tumors=20 are characteristically more acidic than surrounding normal tissue = (52),=20 CQ derivatives may preferentially accumulate in tumor tissue and = display=20 greater efficacy in the inhibition of autophagy in tumor versus = normal=20 tissue. Systemic administration of CQ at doses roughly equivalent = to human=20 doses used to treat malaria or rheumatoid arthritis was well = tolerated for=20 up to 20 days in mice. Although CQ has been reported to have a = variety of=20 additional cellular effects in addition to its ability to suppress = autophagy, the ability of low doses of CQ to enhance p53-induced = apoptosis=20 was dependent on its effects on autophagy. While ATG5 = shRNA=20 independently enhanced p53-induced cell death, no further = enhancement of=20 cell death was observed when tumor cells expressing ATG5 = shRNA=20 were treated with low doses of CQ. However, at high doses (10 = =CE=BCM or=20 greater), CQ treatment may have autophagy-independent effects=20 (Supplemental Figure 1).

Although CQ derivatives such as HCQ at maximally tolerated = doses may=20 achieve a peak blood concentration approaching 10 =CE=BCM, = numerous=20 pharmacokinetic studies of HCQ as a single agent at the standard = doses=20 used in rheumatoid arthritis have determined that steady-state = blood=20 concentrations are in the range of 2=E2=80=933 =CE=BCM (53,=20 54).=20 Together, these data provide the rationale for further = investigation of=20 combination regimens including CQ derivatives and systemic = chemotherapy=20 and/or radiation in order to enhance the therapeutic efficacy of = existing=20 cancer therapies. The data suggest that the development of more = specific=20 autophagy inhibitors may be of clinical benefit if they can be = utilized in=20 combination with apoptosis-inducing agents.

Supplementary=20 Material

References

Methods

Tumor generation and tissue=20 isolation.

All experiments were performed in accordance with = approved=20 animal safety protocols. Approval for animal care and use for = these=20 experiments was provided by the Institutional Animal Care and Use=20 Committee (IACUC) at the University of Pennsylvania.=20 p53ER^TAM/p53ER^TAM mice were created = by M.A.=20 Christophorou, D. Martin-Zanca (BRI-Basic Research Program, = National=20 Cancer Institute-Frederick Cancer Research Facility, Bethesda, = Maryland,=20 USA), and G.I. Evan. All experiments were carried out using 8- to=20 10-week-old C57BL/6=C3=97129F1 mice obtained from The Jackson = Laboratory. Bone=20 marrow cell harvest and production of bone marrow=E2=80=93derived = neoplasms=20 followed the protocol previously described (16).=20 After primary tumor formation, tumor cells were harvested in = ice-cold PBS=20 by passage through a 70-=CE=BCm nylon mesh (BD Biosciences) and = expanded in=20 vivo by subcutaneous injection into the flanks of syngeneic mice. = For=20 tissue analysis, all animals were sacrificed individually by = CO₂₌₂₀asphyxiation and tissue was harvested immediately. Tumors = were=20 harvested in ice-cold PBS. For each tumor, sections of visually = viable=20 tumor tissue were fixed in 10% formalin for preparation of=20 paraffin-embedded sections and glutaraldehyde for electron = microscopy (see=20 below). Tumor cell lysates were achieved through manual agitation = of=20 remaining tumor tissue in RIPA buffer.=20

Drug administration and tumor=20 measurements.

For TAM treatment, the hormone powder = (Sigma-Aldrich)=20 was dispersed, via sonication, in peanut oil (Sigma-Aldrich) at a=20 concentration of 10 mg/ml. The administration of TAM was done via = daily=20 i.p. injections at the dose of 1 mg per mouse. CQ (Sigma-Aldrich) = and HCQ=20 (Spectrum Chemicals Ltd.) were both dissolved in PBS and = administered i.p.=20 For in vitro studies, CQ was dissolved in PBS. hTAM = (Sigma-Aldrich) was=20 dissolved in ethanol. Cyclophosphamide (Sigma-Aldrich) was = dissolved in=20 PBS. MNNG (Sigma-Aldrich) was dissolved in DMSO. Methyl pyruvate = was=20 diluted in PBS (Sigma-Aldrich). For experiments involving MNNG = treatment=20 of cells in vitro, cells were resuspended in RPMI containing 10% = FBS with=20 indicated drugs and incubated at 37=C2=B0C for 15 minutes. Cells = were spun down=20 and resuspended in fresh media with LPS and IL-7 at appropriate = doses =C2=B1 CQ=20 as indicated. Cells were re-treated in this manner daily. Tumors = were=20 measured on a daily basis using calipers, and tumor volume was = calculated=20 using the following formula: (mm³) =3D A = =C3=97 B =C3=97=20 [(A + B)/2]. A and B were the = largest=20 measurements of length and width, respectively, for each tumor.=20

Cell culture.

For in vitro = experiments, 1 primary Myc/p53ER^TAM tumor was=20 harvested in cold PBS, and tumor cells were strained through a = 70-=CE=BCm nylon=20 mesh (BD Biosciences) to isolate a bulk population of tumor cells. = Cells=20 were then frozen in aliquots for future experiments. All in vitro=20 experiments were done in complete medium consisting of RPMI 1640 = medium=20 (Invitrogen) supplemented with 10% heat-inactivated FBS (Gemini=20 Bio-Products), 10 U/ml penicillin/streptomycin, and 2 mM l-glutamine (Invitrogen). Also, 10 = =CE=BCg/ml=20 lipopolysaccharide (Sigma-Aldrich) and 0.2 ng/ml IL-7 (R&D = Systems)=20 were added daily. For all in vitro experiments, media plus = supplements and=20 drug treatments were changed daily. Cell number was assessed by = using a=20 Coulter Z2 particle analyzer or trypan blue exclusion. For MTS = assays, 2 =C3=97=20 10⁵ cells/well were plated in 96-well plates in RPMI = medium=20 containing IL-7, LPS, and the indicated drug treatments. At 24 = hours, the=20 MTS reagent supplied in CellTiter 96 AQueous Assay (Promega) was = added and=20 the results were analyzed according to the manufacturer=E2=80=99s = recommendations.=20 The p53 ^+/+, = p53^{=E2=80=93/=E2=80=93},=20 p53^+/+GFP-LC3, and = p53^{=E2=80=93/=E2=80=93}GFP-LC3=20 MEF cell lines were passaged in DMEM medium supplemented with 10%=20 heat-inactivated FBS (Gemini Bio-Products), 10 U/ml=20 penicillin/streptomycin, and 2 mM l-glutamine (Invitrogen).=20

Immunoblotting.

Cultured = cells were=20 lysed in RIPA buffer. Tumor lysates were obtained by manual = agitation of=20 tumor tissue and lysis in RIPA. Lysates were standardized for = protein=20 content and resolved by SDS-PAGE on 14% NuPAGE gels (Invitrogen).=20 Nitrocellulose blots were probed with antibodies against cleaved = caspase-3=20 (rabbit monoclonal antibody, 1:000; Cell Signaling Technology); = anti-actin=20 (mouse monoclonal antibody, 1:10,000; Sigma-Aldrich); and = anti-ATG5=20 (rabbit polyclonal antibody, 1:2,000; gift from N. Mizushima, = Tokyo=20 Medical and Dental University, Tokyo, Japan).

Electron microscopy = quantification of=20 autophagosomes and apoptosis.

Tissue obtained from tumors was = immediately fixed with 2.5% glutaraldehyde/2% formaldehyde with = 0.1 M=20 sodium cacodylate and stored at 4=C2=B0C until embedding. Cells = were postfixed=20 with 2% osmium tetroxide; this was followed by an increasing = gradient=20 dehydration step using ethanol and propylene oxide. Cells were = then=20 embedded in LX-112 medium (Ladd), and sections were cut ultrathin = (90 nm),=20 placed on uncoated copper grids, and stained with 0.2% lead = citrate and 1%=20 uranyl acetate. Images were examined with a JEOL-1010 electron = microscope=20 (JEOL) at 80 kV. For quantification of viable cells using electron = micrographs of tumor tissue, high-powered micrographs = (=C3=9712,000=E2=80=9320,000) of=20 25 single cells from multiple distinct low-powered fields in each = tumor=20 were obtained. Cells were considered nonapoptotic if the integrity = of the=20 nuclear and cytoplasmic membrane was maintained. For = quantification of=20 apoptotic cells, cells with cytoplasmic and nuclear blebbing and = condensed=20 chromatin or apoptotic bodies were scored as apoptotic. For = quantification=20 of autophagic vesicles per viable cell, the number of = double-membrane=20 vesicles per nonapoptotic cell was scored. Data are presented as = mean =C2=B1=20 SD.

TUNEL staining and fluorescence = imaging.

TUNEL staining was performed using the In Situ Cell = Death=20 Detection Kit, TMR Red (Roche Diagnostics) on paraffin-embedded = tissue=20 harvested from tumors per manufacturer=E2=80=99s instructions. = DAPI counterstain=20 was used to quantify cells with intact nuclei. The percentage of=20 TUNEL-positive cells was calculated by dividing the number of=20 TUNEL-positive cells by the number of DAPI-positive nuclei at = =C3=97100=20 magnification for 4 fields for each tumor sampled. For GFP-LC3=20 fluorescence imaging, Myc/p53ER^TAM = /GFP-LC3,=20 p53^+/+GFP-LC3, and = p53^{=E2=80=93/=E2=80=93}GFP-LC3=20 (see below) cells were exposed to the indicated treatments and = fixed with=20 4% paraformaldehyde for 30 minutes at room temperature, washed 3 = times,=20 and centrifuged onto slides. DAPI counterstain was used to = identify cells=20 with intact nuclei. All fluorescence imaging was performed and = digitally=20 captured at =C3=97100 magnification on a Nikon Eclipse E800 = fluorescent=20 microscope.=20

Constructs, retroviral = infection, and RNA=20 interference.

The U6 promoter and hairpin sequence of the = shRNA=20 nontarget vector pLKO-puro (Sigma-Aldrich) was cloned into TOPO = pCR 2.1=20 (Invitrogen), and the BamHI/SnaBI fragment was excised and cloned = into the=20 pKD expression vector to create HC vector. Two distinct shRNA = sequences=20 against ATG5 (shATG5 h2, shATG5 h7) were generated and = cloned=20 into the pKD expression vector (constructed from pBABE-GFP) as = previously=20 described (9).=20 The plasmid MIGR1/GFP-LC3 was constructed by cloning an XhoI = site=20 5=E2=80=B2 to the GFP-LC3 coding sequence of the pEGFP-C1/LC3 = vector (generous=20 gift of T. Yoshimori, CREST, Japan Science and Technology Agency,=20 Kawaguchi-Saitama, Japan). The XhoI/EcoRI = fragment=20 containing the coding region of the GFP-LC3 fusion gene = was=20 inserted into the multiple cloning site of MIGR1 to generate the=20 MIGR1/GFP-LC3 plasmid. For production of high-titer retrovirus, = 293T cells=20 were cotransfected with retroviral vector (5 =CE=BCg) plus helper = DNA (2.5 =CE=BCg)=20 using Lipofectamine 2000 (Invitrogen). The following retroviral = vectors=20 were used: MIGR1/GFP-LC3, pKD, pKD/HC, pKD/shATG5 h2, and = pKD/shATG5 h7.=20 Conditioned media was harvested and filtered through a = 0.45-=CE=BCM filter.=20 Culture supernatants were then used to transduce=20 Myc/p53ER^TAM cells, p53^+/+ = MEFs,=20 and p53^{=E2=80=93/=E2=80=93}MEFs. Next, 2 =C3=97 = 10⁶ cells were=20 plated in 1 ml of conditioned media containing MIGR1/GFP-LC3, pKD, = pKD/HC,=20 pKD/shATG5 h2, or pKD/shATG5 h7 in the presence of 8 =CE=BCg/ml = hexadimethrine=20 bromide (Polybrene; Sigma-Aldrich). For = Myc/p53ER^TAM=20 cells, fresh IL-7 and LPS were added at the indicated = concentrations in a=20 24-well plate. Adherent cells were infected and incubated for = 4=E2=80=935 hours.=20 For suspension cells, culture plates were spun at 1,015 g = for 1=20 hour at room temperature and then incubated at 37=C2=B0C for 2 = hours. Infection=20 was repeated in this fashion 3 times. Cells were then resuspended = in the=20 appropriate medium and expanded in culture for 3 days. Transduced = cells=20 were sorted for GFP-positive cells (MoFlo; Cytomation) and further = cultured.=20

Statistics.

Means were = compared=20 using the 2-tailed Student=E2=80=99s t test. P = < 0.05 was=20 considered statistically significant in all calculations. All data = analyses were performed using GraphPad QuickCalcs version 1.=20

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Supplementary Material

Supplemental data

Click=20 here to view.^=
(209K)

Acknowledgments

The authors would like to thank Neelima Shah for technical = assistance=20 with electron microscopy and Qian-Chun Yu, Hongwei Yu, and Yan = Wang for=20 technical assistance with tissue processing. We also would like to = thank=20 members of the Thompson Laboratory, especially Roland Knoblauch, = Russell=20 Jones, Monica Buzzai, and Fangping Zhao, for helpful discussions. = Grant=20 support was provided by the NIH (R25-CA87812 to R.K. Amaravadi; = R01-CA=20 102709 to D. Yu and A. Thomas-Tikhonenko; and R01-CA104838-01A1 to = T. Bui=20 and C.B. Thompson) and the Leukemia and Lymphoma Society (to J.J. = Lum).=20

Footnotes

Nonstandard abbreviations used:=20 BECN1, beclin 1; CQ, chloroquine; ER, estrogen = receptor;=20 h2, hairpin 2; h7, hairpin 7; HC, hairpin control; HCQ,=20 hydroxychloroquine; hTAM, 4-hydroxytamoxifen; LC3, mammalian = homolog of=20 yeast Atg8; MEF, mouse embryonic fibroblast; MNNG,=20 N-methyl-N=E2=80=B2-nitro-N-nitrosoguanidine; shRNA, short hairpin = RNA; TAM,=20 tamoxifen.

Conflict of interest: The authors = have=20 declared that no conflict of interest exists.

Citation for this article: J. = Clin.=20 Invest. 117:326=E2=80=93336 (2007). = doi:10.1172/JCI28833=20

Supplementary=20 Material

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Articles=20 from The Journal of = Clinical=20 Investigation are provided here courtesy of
American = Society=20 for Clinical Investigation

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window.focus)=0A= return;=0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= w =3D = window.open("",windowname,"scrollbars,resizable,dependent=3Dyes" + = sizestring);=0A= w.focus();=0A= link.target=3Dwindowname;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function focuswin(windowname) =0A= {=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=0A= return true;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=0A= }catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! 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