c-Abl-independent p73 stabilization during gemcitabine- or 4′-thio-β-d-arabinofuranosylcytosine–induced apoptosis in wild-type and p53-null colorectal cancer cells
Nucleoside anticancer drugs like gemcitabine (2′-deoxy-2′,2′-difluorocytidine) are potent inducers of p53, and ectopic expression of wild-type p53 sensitizes cells to these agents. However, it is also known that nucleosides are efficient activators of apoptosis in tumor cells that do not express a f...
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Veröffentlicht in: | Molecular cancer therapeutics 2006-02, Vol.5 (2), p.400-410 |
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Zusammenfassung: | Nucleoside anticancer drugs like gemcitabine (2′-deoxy-2′,2′-difluorocytidine) are potent inducers of p53, and ectopic expression
of wild-type p53 sensitizes cells to these agents. However, it is also known that nucleosides are efficient activators of
apoptosis in tumor cells that do not express a functional p53. To clarify this issue, we examined the effects of gemcitabine
and 4′-thio-β- d -arabinofuranosylcytosine (T-ara-C) on p73, a structural and functional homologue of p53, whose activation could also account
for nucleoside-induced apoptosis because no functionally significant mutations of p73 have been reported in cancers. Acute
treatment of HCT 116 colon carcinoma cells with gemcitabine or T-ara-C induced marked cytotoxicity and cleavage of caspase-3
and poly(ADP-ribose) polymerase. T-ara-C and gemcitabine markedly induced p53 accumulation as well as increased levels of
phospho-p53 (Ser15/Ser20/Ser46) and induced its binding to a consensus p53 response element. Despite robust activation of
p53 by T-ara-C and gemcitabine, we found that wild-type and p53−/− HCT 116 cells exhibited almost equivalent sensitivity towards
these nucleosides. Examination of p73 revealed that T-ara-C and gemcitabine markedly increased p73 protein levels and p73
DNA-binding activities in both p53−/− and wild-type cells. Furthermore, T-ara-C- and gemcitabine-induced increases in p73
levels occur due to a decrease in p73 protein turnover. RNA interference studies show that nucleoside-induced p73 increases
are independent of c-Abl, a nucleoside-activated kinase recently implicated in p73 stabilization. HCT 116 lines, wherein the
downstream p53/p73 targets Bax and PUMA (p53 up-regulated modulator of apoptosis) were deleted, were less sensitive to T-ara-C
and gemcitabine. Together, these studies indicate that c-Abl-independent p73 stabilization pathways could account for the
p53-independent mechanisms in nucleoside-induced apoptosis. [Mol Cancer Ther 2006;5(2):400–10] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0409 |