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Spatiotemporal activation of caspase-dependent and -independent pathways in staurosporine-induced apoptosis of p53wt and p53mt human cervical carcinoma cells.

Abstract：

BACKGROUND INFORMATION:Caspase-dependent and -independent death mechanisms are involved in apoptosis in a variety of human carcinoma cells treated with antineoplastic compounds. Our laboratory has reported that p53 is a key contributor of mitochondrial apoptosis in cervical carcinoma cells after staurosporine exposure. However, higher mitochondrial membrane potential dissipation and greater DNA fragmentation were observed in p53wt (wild-type p53) HeLa cells compared with p53mt (mutated p53) C-33A cells. Here, we have studied events linked to the mitochondrial apoptotic pathway. RESULTS:Staurosporine can induce death of HeLa cells via a cytochrome c/caspase-9/caspase-3 mitochondrial-dependent apoptotic pathway and via a delayed caspase-independent pathway. In contrast with p53wt cells, p53mt C-33A cells exhibit firstly caspase-8 activation leading to caspase-3 activation and Bid cleavage followed by cytochrome c release. Attenuation of PARP-1 [poly(ADP-ribose) polymerase-1] cleavage as well as oligonucleosomal DNA fragmentation in the presence of z-VAD-fmk points toward a major involvement of a caspase-dependent pathway in staurosporine-induced apoptosis in p53wt HeLa cells, which is not the case in p53mt C-33A cells. Meanwhile, the use of 3-aminobenzamide, a PARP-1 inhibitor known to prevent AIF (apoptosis-inducing factor) release, significantly decreases staurosporine-induced death in these p53mt carcinoma cells, suggesting a preferential implication of caspase-independent apoptosis. On the other hand, we show that p53, whose activity is modulated by pifithrin-alpha, isolated as a suppressor of p53-mediated transactivation, or by PRIMA-1 (p53 reactivation and induction of massive apoptosis), that reactivates mutant p53, causes cytochrome c release as well as mitochondrio-nuclear AIF translocation in staurosporine-induced apoptosis of cervical carcinoma cells. CONCLUSIONS:The present paper highlights that staurosporine engages the intrinsic mitochondrial apoptotic pathway via caspase-8 or caspase-9 signalling cascades and via caspase-independent cell death, as well as through p53 activity.

journal_name

Biol Cell

journal_title

Biology of the cell

authors

Nicolier M,Decrion-Barthod AZ,Launay S,Prétet JL,Mougin C

doi

10.1042/BC20080164

subject

Has Abstract

pub_date

2009-06-04 00:00:00

pages

455-67

issue

eissn

0248-4900

issn

1768-322X

pii

BC20080164

journal_volume

101

pub_type

杂志文章

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Spatiotemporal activation of caspase-dependent and -independent pathways in staurosporine-induced apoptosis of p53wt and p53mt human cervical carcinoma cells.