Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide

Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of prostate cancer characterized by high levels of endoplasmic reticulum (ER) stress and metabolic dysregulation. The subsequential metabolic adaptations in the cancer cells reinforce survival mechanisms that contribute to therapy resistance and metastasis. The oncogenic driver neuroblastoma-derived MYC (MYCN) exacerbates ER stress by increasing calcium ion efflux from the ER into mitochondria, promoting glycolytic and oxidative stress. Here, we demonstrate that nitric oxide (NO) signaling is dysregulated in NEPC, thus allowing impaired S-nitrosylation of MYCN and uncontrolled ER stress. We show that exogenous NO supplementation restores MYCN S-nitrosylation at Cys4, Cys186, and Cys464. This re-establishment significantly reduces ER stress markers, inhibits the unfolded protein response (UPR), and suppresses NEPC cell proliferation and colony formation in vitro. In an orthotopic NEPC murine model, NO treatment led to a substantial reduction in tumor burden and metastasis to the liver and brain, with corresponding decreases in chromogranin and synaptophysin expression. Additionally, NO supplementation attenuated glycolytic stress by limiting calcium-mediated mitochondrial dysfunction and modulating metabolic pathways. Our findings uncover a direct mechanistic link between MYCN-driven ER stress and NEPC progression and highlight NO supplementation as a potential therapeutic strategy to counteract lineage plasticity and metabolic adaptations in NEPC. These results provide a compelling rationale for further investigation into NO-based therapies as a novel intervention for NEPC, a cancer subtype with limited treatment options and poor prognosis.