Abstract A44: p53 protects against MG132-induced apoptosis in a cell state-dependent manner.

Abstract

Abstract Proteasome inhibition is 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 unknown. The tumor suppressor protein p53 plays an essential role in establishing and maintaining quiescence in human cells. It also regulates several cell survival mechanisms, such as cell cycle arrest, autophagy, and activation of detoxifying enzymes. Here, we investigate the role of p53 in establishing resistance against proteasome inhibitors in quiescent cells. We found that MG132 (a known proteasome inhibitor) treatment induces the accumulation of p53 and its downstream target p21 more in quiescent 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 either nuclear or cytoplasmic p53 activity. These findings suggest that proliferating and quiescent cells depend on different p53-induced survival mechanisms to be protected from proteasome inhibition. 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. Citation Format: Aster Legesse-Miller, Jacky Ho Wa Cheng. p53 protects against MG132-induced apoptosis in a cell state-dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A44.