Targeting Endoplasmic Reticulum Stress and Nitroso-Redox Imbalance in Neuroendocrine Prostate Cancer: The Therapeutic Role of Nitric Oxide

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of prostate cancer. Current standard-of-care treatment for NEPC involves chemotherapies, which largely exert their cytotoxic effects by forming DNA crosslinks, disrupting DNA replication and transcription in NEPC cells. However, these therapies are often met with resistance, partly due to increased endoplasmic reticulum (ER) stress, which facilitates cancer cell survival and adaptive mechanisms. Despite its critical role, the molecular landscape underlying ER stress in NEPC remains inadequately understood. Here we showed that ER stress is intimately linked to the metabolic reprogramming of NEPC cells, a process that supports their transition from adenocarcinoma to a neuroendocrine phenotype. We identified MYCN as a key driver of this process, promoting unfolded protein response (UPR) elements that enhance ER stress by increasing the efflux of calcium ions through the ER which later is absorbed by the mitochondria and assist in increasing the overall glycolytic stress, thereby adding to the extended survival and metastatic potential of an NEPC cell. Our previous studies highlighted the importance of S-nitrosylation as a protein modification that is dysregulated in high-grade PCa. In this context, structural analysis of MYCN revealed potential S-nitrosylation sites at the positions Cys4, 186, and 464, respectively. However, similar to the castration-resistant stage, this modification is hindered in NEPC due to impaired nitric oxide (NO) production from dysregulated endothelial nitric oxide synthases (eNOS). We found that exogenous NO supplementation S-nitrosylates MYCN, reducing its binding to protein molecules which are essential to assist with increasing ER stress in NEPC cells. Exogenous supplementation of NO reduced the overall tumor burden in the mice harboring orthotopic NEPC cells and reduced the metastasis to the brain and liver. In conclusion, the findings from this study enrich our understanding of the mechanisms driving the ER stress responses in NEPC phenotype and how NO supplementation could pave the way as potential therapeutics for this challenging cancer. HIGHLIGHTSO_LIEndoplasmic reticulum (ER) stress is intricately linked to metabolic reprogramming, which supports the transition from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC). C_LIO_LIMYCN increases the ER stress in NEPC cells and is correlated with increased nitroso-redox imbalance. C_LIO_LIStructural analysis reveals potential S-nitrosylation sites on MYCN. Exogenous nitric oxide (NO) supplementation induces S-nitrosylation, disrupting MYCNs role in enhancing ER stress. C_LIO_LINO supplementation reduced tumor burden and metastasis in NEPC-bearing mice, highlighting its potential as a therapeutic avenue for NEPC. C_LIO_LIExogenous NO supplementation inhibits ER stress by targeting unfolded protein response (UPR) elements and decreasing calcium ion efflux, inhibiting the glycolytic stress in NEPC. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/624202v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1fb292forg.highwire.dtl.DTLVardef@4d00f7org.highwire.dtl.DTLVardef@17a7f43org.highwire.dtl.DTLVardef@1393286_HPS_FORMAT_FIGEXP M_FIG C_FIG