Abstract 886: Reduced p53 promotes survivorship in response to oxidative stress

Cellular oxidative stress is commonly observed in aggressive cancers and initiates mechanisms that enable adaptation and survival in tumor cells. Traditionally, reactive oxygen species (ROS) have been thought to be cellular damaging agents lacking a physiological function; however, increased ROS generation and oxidative damage are connected to multiple diseases, including neurodegenerative disorders, aging, and cancer. The p53 tumor suppressor gene is often mutated in most cancers, and under normal conditions, functions to initiate apoptosis in response to oxidative stress. Thus, absence of p53, or a mutation rendering it non-functionality, can aid in tumor cell survival. We determined whether prostate cancer cells survived oxidative stress, and whether survivorship was enhanced by the absence of p53. Measurement of ROS generation in serum-starved and serum-treated PC3, DU145 and LNCaP prostate cancer cell lines were performed to demonstrate induction of oxidative stress. We observed that serum-starved cells generated more ROS and oxidative stress compared to cells in serum, and that cells further adapted to stress with the addition of hydrogen peroxide. To further determine adaptation to oxidative stress, we assayed for Annexin-V apoptosis. Previous data in the lab demonstrated that neither cell line demonstrated robust proliferation under oxidative stress; however, DU145 and PC3 cells demonstrated better survival and adaptation to oxidative stress through lower apoptosis profiles compared to LNCaP cells. Survivorship of oxidative stress may be attributed to p53 as LNCaP cells reportedly have functional p53 in literature compared to DU145 and PC3. Therefore, we immunoblotted for phosphorylated p53 expression in response to oxidative stress. To further demonstrate non-functional p53 promotes survivorship in response to oxidative stress, we performed a genomic knockdown of p53 via siRNA and demonstrated survivorship to oxidative stress may be attributed to non-functional p53 via live/dead cell viability assay. Our results correlate with studies demonstrating tumor cell resistance to ROS-mediated cell death contributing to more aggressive phenotypes and activation of anti-apoptotic events. Therefore, our study will extend our understanding of the functionality of p53 in oxidative stress adaptation and cancer cell survival. Moreover, in the future, we will investigate the inverse relationship between p53 and pro-survival factors like nuclear factor kappa B (NF-κB) in oxidative stress adaptation and cancer cell survival.

Acknowledgements: These studies were supported by the NIH/NIGMS/RISE #5R25GM060414-15 and NIH/NIHMD/RCMI #5G12MD007590.

Note: This abstract was not presented at the meeting.

Citation Format: Jada R. Carter, Elshaddai White, Cimona V. Hinton. Reduced p53 promotes survivorship in response to oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 886.