Abstract 1956: Stress-mediated reactive oxygen species from mitochondria dysregulates the tumor microenvironment in prostate cancer of African American men

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men in United States. African American men (AAM) have higher rates of PCa incidence and mortality compared with European American men (EAM). While socioeconomics, access to optimal care and life-style factors contribute towards these disparities, underlying biologic differences in AAM remain important drivers of PCa disparities. In the current work, we aimed to explore the interplay between oxidative stress and inflammatory signaling in promoting progression of PCa in AAM. Oxidative stress results from excessive reactive oxygen species (ROS) generated mainly via membrane bound oxidases, peroxisomes or the mitochondrial electron transport chain (ETC). We performed a robust comparative genomics to determine whether there is a race dependent expression of genes related to ROS in publicly available PCa datasets. We then prospectively examined the differential gene expression of these genesets in PCa from clinically matched AAM and EAM in the VANDAAM prospective study. VANDAAM is a validation study of DecipherTM genomic testing in 243 men with localized PCa. We then combined computational and experimental approaches to explore the molecular mechanisms and consequences of exacerbated oxidative stress. We found that ETC complex I, III related genes are the most differentially expressed in AAM compared with EAM. To examine whether AAM vs EAM cell lines exhibits differential sensitivity to ETC modulation, we blocked key ETC enzymes using complex I inhibitor, rotenone, and complex III inhibitor, antimycin A. We used 2 types of mitochondria-specific labels that distinguish respiring and ROS-generating mitochondria. While the relative levels of respiring mitochondria remain constant, we found that antimycin A induced higher level of mitochondrial ROS in AAM PCa cell lines compared with EAM PCa cell lines. To understand the interplay between mitochondrial ETC complex I & III and immune microenvironment, we computed the correlational discordance of ETC complex I & III expression scores and expression of >1200 immune-related genes between AAM vs EAM in VANDAAM cohort. These analyses suggest that ETC complex I & III correlate with several immunosuppressive genes including the macrophage markers CD68 and CD163 and T cell exhaustion markers. In addition, intersecting discordant genes from several datasets suggests enrichment of inflammatory cytokines and type I interferon signature which we then validated using ex vivo culture of PCa tissues. In summary, we discovered a role of mitochondrial electron transport chain in regulating inflammatory circuits in PCa of AAM. Unraveling roles of mitochondria in promoting immune suppression will have significant impact on understanding the intersection between social pressures and biological stress responses. Citation Format: Asmaa El-Kenawi, Ryan Putney, Shivanshu Awasthi, Amparo Serna, Corrado Caslini, Jasreman Dhillon, Kosj Yamoah. Stress-mediated reactive oxygen species from mitochondria dysregulates the tumor microenvironment in prostate cancer of African American men [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 1956.