Abstract 5374: Metabolic reprogramming regulates tyrosine receptor kinase c-Met in prostate cancer

Mitochondrial metabolic reprogramming is known to regulate oncopathways. To understand mitochondria-regulated oncopathways in prostate cancer (PC), we used a transmitochondrial cybrid system. Under a benign prostate cell line PNT1a, cybrids were generated after cytoplasmic fusion from PNT1a (PNT1/PNT1) and PC cell line PC3 (PC3/PNT1). PC3/PNT1 cybrids showed increased tumor stemness, metastasis, and mitochondrial activity with enhanced OXPHOS and fatty acid oxidation (FAO) compared to PNT1/PNT1 cybrids. RNASeq analysis of cybrids identified increased mRNA expression of Mesenchymal Epithelial Transition receptor (c-Met) in cybrids with cancer mitochondria. c-Met is a receptor tyrosine kinase (RTK) and an essential receptor that regulates multiple cellular signaling and homeostasis in mammalian cells. c-Met is often over-expressed in several types of cancers and is thus considered a potential therapeutic target. c-Met activation is known to increase glucose metabolism by upregulating the expression of glycolysis-related genes such as GLUT-1, HK-2, PFK-1, LDH-1, and SIRT1 in tumor cells. However, how tumor metabolism affects c-Met expression is unclear. Etomoxir (FAO inhibitor) and Atovaquone (OXPHOS inhibitor) suppressed c-Met protein expression through the mTOR-P70S6K pathway in PC cells. Rapamycin (mTOR inhibitor) reduced c-Met expression in PC3 and DU145 PC cells. Preliminary analysis suggests that the mitochondrial inhibitors and capmatinib, an FDA-approved c-Met inhibitor, have a combinatorial effect. Collectively, this study suggests that mitochondrial metabolic reprogramming to FAO in PC upregulates c-Met activity. Citation Format: Songyeon Ahn, Tagari Samanta, Junhyoung Park, Benny A. Kaipparettu. Metabolic reprogramming regulates tyrosine receptor kinase c-Met in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5374.