CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer

• Published in: PloS one Vol. 19; no. 5; p. e0300413
• Main Authors: Azur, Romie Angelo G, Olarte, Kevin Christian V, Ybañez, Weand S, Ocampo, Alessandria Maeve M, Bagamasbad, Pia D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-05-2024; Public Library of Science (PLoS)
• Subjects: Androgens; Biology and Life Sciences; Biosynthesis; Cancer therapies; Castration; Cell culture; Cell Differentiation; Cell growth; Cell Line, Tumor; Differentiation; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Humans; Iron; Iron - metabolism; Iron compounds; Maintenance; Male; Medicine and Health Sciences; Metabolism; Metastases; Metastasis; Neuroendocrine Cells - metabolism; Neuroendocrine Cells - pathology; Neuropeptides; Paracrine signalling; Phenotype; Phenotypes; Physiological aspects; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Steroids; Tumor cell lines; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0300413

Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.