BCL2 Suppresses PARP1 Function and Nonapoptotic Cell Death

Abstract

BCL2 suppresses apoptosis by binding the BH3 domain of pro-apoptotic 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 anti-apoptotic protein BCL2 and the enzyme poly(ADP) ribose polymerase 1 (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, re-establishing PARP1 activity and DNA repair and promoting non-apoptotic cell death. This form of cell death was unaffected by resistance to single-agent ABT-737 that results from upregulation of anti-apoptotic BCL2 family members. Based on 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 90-100%, and these effects were reversed by ABT-737. Taken together, our findings demonstrate 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.

BCL2 is an independent predictor of outcome in basal-like triple-negative breast cancers treated with adjuvant anthracycline-based chemotherapy

“…However, high levels of BCL2 expression block apoptosis, allowing the tumor cells to survive. This conclusion is supported by the observation that anti-BCL2 therapy (ABT-737) induced characteristics of apoptosis in vitro when applied in conjunction with the topoisomerase II poison etoposide [11]. An association between low levels of BCL2 expression and an enhanced anthracycline response (pCR) in neoadjuvant settings has also been reported by others [13,15,32].…”

“…It also performs other functions, such as promoting cell growth and proliferation [9][10][11]. Preclinical data showed that BCL2 expression was associated with resistance to anthracycline doxorubicin [12].…”

Luteolin Attenuates Doxorubicin-Induced Cytotoxicity to MCF-7 Human Breast Cancer Cells

“…Recent studies have reported that Bcl-2 has multiple functions, including regulation of calcium homeostasis and mitochondrial dynamics, as well as suppression of nonapoptotic cell death, suggesting that various functions of Bcl-2 are involved in the attenuation of doxorubicin-induced cell toxicity of luteolin. 32,33) Our findings indicate that luteolin attenuates the pharmacological action of doxorubicin in MCF-7 cells, depending on the experimental conditions.…”

PARP-1 Modulates Amyloid Beta Peptide-Induced Neuronal Damage

“…Recently, Dutta et al [66] have demonstrated that Bcl-2 may influence PARP activity both in vitro and in cancer cells by a direct interaction with PARP-1. The overall relationship between PARP-1 and Bcl-2 may depend on the various inner environment of different cell lines and on the pathological condition.…”