Zinc Inhibits Expression of Androgen Receptor to Suppress Growth of Prostate Cancer Cells

• Published in: International journal of molecular sciences 2018-10, Vol.19 (10), p.3062
• Main Authors: To, Phuong Kim, Do, Manh-Hung, Cho, Young-Suk, Kwon, Se-Young, Kim, Min Soo, Jung, Chaeyong
• Format: Article
• Language: English
• Subjects: androgen receptor; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Humans; Male; Mice; Mice, Inbred C57BL; prostate cancer; Prostate-Specific Antigen - genetics; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; zinc; Zinc Compounds - pharmacology; Zinc Compounds - therapeutic use
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms19103062

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of zinc and its underlying mechanism in the growth of PCa. ZnCl₂ suppressed the proliferation of androgen receptor (AR)-retaining PCa cells, whereas it did not affect AR-deficient PCa cells. In LNCaP and TRAMP-C2 cells, zinc downregulated the expression of AR in a dose- and time-dependent fashion. Zinc-mediated AR suppression accordingly inhibited the androgen-mediated transactivation and expression of the androgen target, prostate specific antigen (PSA). This phenomenon resulted from facilitated protein degradation, not transcriptional control. In studies using mice bearing TRAMP-C2 subcutaneous tumors, the intraperitoneal injection of zinc significantly reduced tumor size. Analyses of both xenograft tumors and normal prostates showed reduced expression of AR and increased cell death. Considering the significant loss of intracellular zinc and the dominant growth-modulating role of AR during PCa development, loss of zinc may be a critical step in the transformation of normal cells to cancer cells. This study provides the underlying mechanism by which zinc functions as a PCa suppressor, and forms the foundation for developing zinc-mediated therapeutics for PCa.