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Induction of
apoptosis in resistant glioma cells by synthetic caspase-activation
Terese Karlsson, Roger
Henriksson and Håkan Hedman
Department of Radiation Sciences, Oncology, Umeå University,
Umeå, Sweden
The detailed mechanisms
behind the resistance of malignant gliomas to therapy are not known.
Inherent resistance to apoptosis
is, however, one plausible explanation.
In the present study we tried to delineate the molecular defects and
to induce apoptosis by inducible caspases in three apparently apoptosis
resistant glioma cell lines.
U-105 MG, U-251 MG, and SF-767 were
resistant to Fas-induced apoptosis as shown by the lack of Fas-induced cell
death, morphological changes,
annexin-V reactivity, Parp cleavage, caspase-3 cleavage, and caspase-3
activation.
The glioma cells showed no
consistent down-regulation of the pro-apoptotic proteins Fas, Fadd, caspase-3,
caspase-8, caspase-9, Apaf-1, Bid,
Bad, or Bax, and no consistent up-regulation of the anti-apoptotic proteins
Bcl-x or Bcl-2.
In U-105 MG, Fas was, however, not detected at the cell surface indicating
intracellular retention.
To assess if the apoptotic blocks
could be by-passed, we introduced the so-called artificial death switches, i.e.,
inducible caspases and Fadd, into
the glioma cells.
Synthetic activation of inducible caspase-3, but not of caspase-8, resulted in
apoptosis in the three glioma cell
lines and inducible Fadd induced apoptosis in SF-767.
The results were consistent with a
block in the apoptotic signaling pathways of glioma cells between caspase-8 and
caspase-3 activation, and that inducible
Fadd could induce caspase-8 independent apoptosis in some cells.
Apparently resistant glioma cells could thus
be induced to undergo apoptosis by activation of appropriate death
switches.
This might have implications for the
design of future therapeutic strategies.
Key words: apoptosis,
caspases, death switch, Fas, glioma
© 2004 Kluwer Academic
Publishers. Printed in the Netherlands.
Source: http://journals.kluweronline.com/article.asp?PIPS=5145793
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