EDNRB negatively regulates glycolysis to exhibit anti-tumor functions in prostate cancer by cGMP/PKG pathway

Prostate cancer (PCa) is the most prevalent cancer in men and the leading cause of cancer-related mortality. Recent studies have highlighted the pivotal role of glycolysis in tumor progression. This study aimed to investigate the involvement of the EDNRB gene and its ligand endothelin 3 (EDN3) in glycolysis in PCa and to elucidate its underlying molecular mechanism. Quantitative reverse transcription PCR (RT-qPCR) and methylation-specific PCR (MSP) were used to probe EDNRB expression and methylation in PCa tissues. Cell proliferation and glycolysis in PCa cells were evaluated using Cell Counting Kit-8 (CCK-8), EDU staining, Seahorse assay, and biochemical kits to analyze the effects of EDN3/EDNRB. The underlying molecular mechanism was further explored through Western blotting. The in vivo effect of EDNRB on tumor growth was examined using a xenograft tumor model. Our findings revealed that EDNRB was hypermethylated and downregulated in PCa tissues and cell lines. Overexpression of EDNRB or EDN3 led to reduced cell proliferation and downregulation of glycolytic markers. EDNRB also decreased the extracellular acidification rate (ECAR) baseline and increased the oxygen consumption rate (OCR) baseline, indicating a shift away from glycolysis. Additionally, the anticancer effects of EDNRB or EDN3 was reversed upon inhibition of the cGMP/PKG pathway. In vivo, enhanced EDNRB expression significantly suppressed tumor growth. Therefore, EDNRB or EDN3 possess anticancer potential in PCa, primarily through the regulation of glycolysis via the cGMP/PKG pathway.