Abstract 1008: Cytoplasmic p53 protects against MG132-induced apoptosis in a cell state-dependent manner

Abstract

Abstract Since the approval of proteasome inhibitor, Bortezomib, for use in multiple myeloma in 2003, pharmacological proteasome inhibitors has been shown to be an important strategy for treating many types of cancer. While proteasome inhibitors induce apoptosis in certain rapidly proliferating cancer cells, some cells enters quiescence and survives. The mechanism by which quiescent cells become resistant to proteasome inhibitors is largely unknown. The tumor suppressor protein p53 plays an essential role in establishing and maintain quiescence in human cells. It also regulates several cell survival mechanisms, including cell cycle arrest, autophagy, and activation of reactive oxygen detoxifying enzymes. Here, we investigated the role of p53 in establishing resistance against proteasome inhibitors in quiescent cells. We found that MG132 (a know proteasome inhibitor) treatment induces the accumulation of p53 and its downstream target p21 more in quiescent cells than in proliferating primary human fibroblasts. shRNA mediated down-regulation of p53 sensitizes both proliferating and quiescent fibroblasts to MG132-mediated apoptosis and cell death, suggesting that p53 plays a protective role in all cell states. Additional experiments demonstrated that proliferating fibroblasts are susceptible to inhibition of cytoplasmic p53 activity, whereas quiescent fibroblasts are sensitive to inhibition of nuclear p53 activity. These findings suggest that p53 induces different protective mechanisms against MG132-mediated cell death, depending of the proliferative state of the cells. Autophagy, an alternative degradation pathway regulated by p53, is also induced in both cell states upon MG132 treatment. Identification of p53-mediated regulatory mechanisms that are activated in quiescent cells in response to proteasome inhibition may help to suggest strategies for improving the effectiveness of proteasome inhibitors in treating cancer. This work was supported by NCI K01 CA128887 to Aster Legesse-Miller. Citation Format: Ho Wa (Jacky) Cheng, Aster Legesse-Miller. Cytoplasmic p53 protects against MG132-induced apoptosis in a cell state-dependent manner. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2015-1008