Abstract 1965: Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance

Abstract

Abstract Compared to European American (EA), African American (AA) men often develop lethal forms of prostate cancer (PCa) and experience high mortality despite having a primary diagnosis of low-risk indolent disease. Understanding the molecular basis of this disparity is thus a dire need for better prevention, accurate monitoring, and guided therapeutics. Aggressive cancer growth is intimately associated with the reprogramming of metabolism and apoptosis, where mitochondrial DNA (mtDNA) alterations play a critical role. In the mitochondrial energy generation cascade, respiratory complex I (RCI) serves as the entry gate to initiate electron transfer through the oxidative phosphorylation system (OXPHOS). Alteration in RCI function could alter metabolism and attenuate apoptosis, hallmarks of malignant progression. Through next-generation sequencing of the entire mitochondrial genome, we identified a prevalence of RCI gene mutations in the AAPCa compared to the EAPCa patients. Among the RCI mutations, a homoplasmic 13709C>G mutation in NADH dehydrogenase 5 (ND5) was identified as the most frequently occurring mtDNA mutation among AA men. Forced expression of the 13709C>G mutation in the mitochondria of the AA-PCa patient-derived MDA PCa 2b and EA-PCa patient-derived LNCaP cells, remarkably enhanced their growth and malignant potential. The increased tumorigenicity was associated with a significant increase in the production of mitochondrial reactive oxygen species (ROS), O2 consumption, overall respiration, and ATP production. The ND5-mutant PCa cells exhibited remarkable resistance to androgen deprivation and docetaxel treatment. Induction of CXCR4, HIF-1α, and NF-kB was also noted in these ND5-mutant PCa cells. In clinical tissue samples, an abundance of CXCR4 protein expression was evident in AA-PCa patients harboring ND5 gene mutation but not in the AA or EA-PCa patients with wild-type ND5. Blockade of CXCR4 expression in the ND5-mutant PCa cells diminished NF-kB activity, thereby suggesting a potential role of the CXCR4/HIF-1α/NF-kB signaling axis in ND5 mutation-driven PCa tumorigenesis. The RCI-ND5 could be an attractive target for therapeutic and biomarker development for the better management of PCa in racially disparate populations. Citation Format: Kunwar Somesh Vikramdeo, Christopher E. Keel, Martin J. Heslin, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta. Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance [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 1965.