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.

• Authors: Magali Nicolier, Anne-Zélie Decrion-Barthod, Sophie Launay, Jean-Luc Prétet, Christiane Mougin
• Journal: Biology of the cell (Biol Cell) Vol. 101 Issue 8 Pg. 455-67 (Jun 04 2009) ISSN: 1768-322X [Electronic] England
• PMID: 19216720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Caspase Inhibitors
• Tumor Suppressor Protein p53
• Caspases
• Staurosporine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma (drug therapy, metabolism, physiopathology)
• Caspase Inhibitors
• Caspases (genetics, metabolism)
• Enzyme Activation (drug effects)
• Female
• Humans
• Mutation
• Signal Transduction (drug effects)
• Staurosporine (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Uterine Cervical Neoplasms (drug therapy, metabolism, physiopathology)