Mcl-1 cleavage and sustained phosphorylation of c-Jun-N-terminal kinase mediate melanoma apoptosis induced by 2-acetyl furanonaphthoquinone: roles of Bcl-2 and p53.

Abstract

2-acetyl furanonaphthoquinone (FNQ) is a naturally occurring drug with enhanced toxicity versus glucose-starved tumor cells, which frequently show topoisomerase II drug resistance. Since loss of p53 tumor suppressor function or overexpression of the anti-apoptotic bcl-2 gene can decrease susceptibility to some cancer therapies, we now investigated the effect of FNQ against genetically matched C8161 melanoma cell lines transduced to express unequal levels of Bcl-2, or engineered to harbour a functional wt p53 for comparison with dominant-negative mutant p53 R175H. Cells with differing p53 genotype showed susceptibility to FNQ. However, this response was attenuated in those overexpressing mutant p53, although a brief p53 induction was early seen in FNQ-treated wt p53 cells. Cells susceptible to FNQ showed cleavage of anti-apoptotic Mcl-1, sustained activation of the c-Jun N-terminal Kinase (p-JNK), and apoptosis-associated PARP fragmentation, all of which were counteracted in bcl-2 overexpressing cells. Suppression of JNK activation with the specific inhibitor, SP600125 also prevented FNQ-mediated cell death. Our data suggests that Bcl-2, persistent JNK phosphorylation and cleavage of anti-apoptotic Mcl-1 are key events controlling susceptibility to FNQ.

• Authors: Manuel Rieber, Mary Strasberg Rieber
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 7 Issue 8 Pg. 1206-11 (Aug 2008) ISSN: 1555-8576 [Electronic] United States
• PMID: 18458532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-acetylfuranonaphthoquinone
• Antineoplastic Agents
• Furans
• Naphthoquinones
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• Mitogen-Activated Protein Kinase 9
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Caspases (genetics, metabolism, pharmacology)
• Cell Line, Tumor
• Furans (pharmacology)
• Humans
• Melanoma (genetics, metabolism)
• Mitogen-Activated Protein Kinase 9 (genetics, metabolism, pharmacology)
• Naphthoquinones (pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism, pharmacology)
• bcl-2-Associated X Protein (genetics, metabolism, pharmacology)