Abstract 2525: Analyzing the role of MDMX for regulating cell death in prostate cancer cells

Abstract

Abstract Prostate cancer (PCa) is the most prominent cancer type and the second leading cause of cancer death among men in the USA. The five-year survival rate for localized PCa is 98% but drops to 31% when PCa spreads to different parts of the body. Various treatment strategies that can induce cell death through different mechanisms are used while treating cancers. In recent years, necroptosis has been established as one of the effective mechanisms of inducing cell death in cancers. Necroptosis can be identified as a regulated form of cell death that can occur independently of executioner caspases. Despite numerous studies on the effects of necroptosis in cancer, it’s role on PCa has not been fully elucidated. In this study, we have evaluated the role of MDMX, a proto-oncogene involved in the negative regulation of p53, in causing cell death through p53-independent mechanisms. We have observed that inhibition of MDMX decreased the cell viability of LNCaP cells in response to 20 µM of NSC (NSC-207895), a MDMX specific inhibitor treatment, in a concentration-dependent manner. MDMX inhibition appears to induce necroptosis in LNCaP prostate cancer cells by elevating the expression of receptor-interacting protein kinase 1 (RIP1), which is a key element of the necroptotic pathway. In general, the necroptosis pathway can trigger two opposing mechanisms in cancer where it can promote tumor migration and metastasis on one hand and can also act as a defensive mechanism on the other hand when apoptosis is disrupted. To further assess the effect of MDMX on cell migration, the LNCaP cells were treated with 20 µM of NSC, which effectively blocked the cancer cell migration for up to 48 h, which was confirmed using the scratch assay. Interestingly, NSC treatment also reduced the expression of Vascular Endothelial Growth Factor A (VEGFA), which is one of the main markers for angiogenesis. Our results show that the p53-independent mechanisms that are activated following MDMX inhibition can regulate both cancer cell migration and angiogenesis. MDMX also seemed to be involved in regulating PCa cell survival through necroptosis. The outcomes of our experiments provide additional knowledge and strategies for making an accurate prognosis and choosing the most suitable therapeutic strategies for offering effective treatments for MDMX-positive PCa. (This research was supported by the Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida) Citation Format: Ahmed Alsarrani, Umamaheswari Natarajan, Samia Alsubhi, Amal Alzahrani, Appu Rathinavelu. Analyzing the role of MDMX for regulating cell death in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2525.