Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma.

Abstract

Tumor necrosis factor (alpha)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (alpha) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor-induced apoptosis via the Bak pathway.

• Authors: Bernhard Gillissen, Jana Wendt, Antje Richter, Anja Richter, Annika Müer, Tim Overkamp, Nina Gebhardt, Robert Preissner, Claus Belka, Bernd Dörken, Peter T Daniel
• Journal: The Journal of cell biology (J Cell Biol) Vol. 188 Issue 6 Pg. 851-62 (Mar 22 2010) ISSN: 1540-8140 [Electronic] United States
• PMID: 20308427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAK1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• TNF-Related Apoptosis-Inducing Ligand
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• bcl-X Protein

Topics

• Apoptosis (drug effects)
• Carcinoma (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (metabolism, pharmacology)
• bcl-2 Homologous Antagonist-Killer Protein (antagonists & inhibitors, metabolism)
• bcl-2-Associated X Protein (deficiency, genetics, metabolism)
• bcl-X Protein (metabolism)