BCL2 suppresses PARP1 function and nonapoptotic cell death.

Abstract

BCL2 suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating outer mitochondrial membrane permeabilization. Many tumor types, including B-cell lymphomas and chronic lymphocytic leukemia, are dependent on BCL2 for survival but become resistant to apoptosis after treatment. Here, we identified a direct interaction between the antiapoptotic protein BCL2 and the enzyme PARP1, which suppresses PARP1 enzymatic activity and inhibits PARP1-dependent DNA repair in diffuse large B-cell lymphoma cells. The BH3 mimetic ABT-737 displaced PARP1 from BCL2 in a dose-dependent manner, reestablishing PARP1 activity and DNA repair and promoting nonapoptotic cell death. This form of cell death was unaffected by resistance to single-agent ABT-737 that results from upregulation of antiapoptotic BCL2 family members. On the basis of the ability of BCL2 to suppress PARP1 function, we hypothesized that ectopic BCL2 expression would kill PARP inhibitor-sensitive cells. Strikingly, BCL2 expression reduced the survival of PARP inhibitor-sensitive breast cancer and lung cancer cells by 90% to 100%, and these effects were reversed by ABT-737. Taken together, our findings show that a novel interaction between BCL2 and PARP1 blocks PARP1 enzymatic activity and suppresses PARP1-dependent repair. Targeted disruption of the BCL2-PARP1 interaction therefore may represent a potential therapeutic approach for BCL2-expressing tumors resistant to apoptosis.

• Authors: Chaitali Dutta, Tovah Day, Nadja Kopp, Diederik van Bodegom, Matthew S Davids, Jeremy Ryan, Liat Bird, Naveen Kommajosyula, Oliver Weigert, Akinori Yoda, Hua Fung, Jennifer R Brown, Geoffrey I Shapiro, Anthony Letai, David M Weinstock
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 16 Pg. 4193-203 (Aug 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22689920 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• ABT-737
• Biphenyl Compounds
• Nitrophenols
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Methylnitronitrosoguanidine
• PARP1 protein, human
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Biphenyl Compounds (pharmacology)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (metabolism, pathology)
• Lymphoma, Large B-Cell, Diffuse (metabolism, pathology)
• Methylnitronitrosoguanidine (pharmacology)
• Mice
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, metabolism)
• Sulfonamides (pharmacology)