p66Shc protein through a redox mechanism enhances the progression of prostate cancer cells towards castration-resistance

• Published in: Free radical biology & medicine 2019-08, Vol.139, p.24-34
• Main Authors: Miller, Dannah R., Ingersoll, Matthew A., Chatterjee, Arpita, Baker, Brian, Shrishrimal, Shashank, Kosmacek, Elizabeth A., Zhu, Yuxiang, Cheng, Pi-Wan, Oberley-Deegan, Rebecca E., Lin, Ming-Fong
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Animals; Antineoplastic Agents - pharmacology; Castration-resistant prostate cancer; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Disease Progression; Drug Resistance, Neoplasm - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Hydrogen Peroxide - pharmacology; Kallikreins - genetics; Kallikreins - metabolism; Lymphatic Metastasis; Male; Mice; Mice, Nude; p66Shc; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostate-Specific Antigen - genetics; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Reactive Oxygen Species - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; ROS; Src Homology 2 Domain-Containing, Transforming Protein 1 - genetics; Src Homology 2 Domain-Containing, Transforming Protein 1 - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2019.05.015

Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in U.S. men due to the development of the castration-resistant (CR) PCa phenotype. A useful cell model for analysis of the molecular mechanism of PCa progression is required for developing targeted therapies toward CR PCa. In this study, we established a PCa cell progressive model in three separate cell lines, of which androgen-independent (AI) cells were derived from respective androgen-sensitive (AS) cells. Those AI PCa cells obtain the biochemical properties of the clinical CR phenotype, including AR and PSA expression as well as enhanced proliferation and tumorigenicity under androgen-deprived conditions. Thus, those AI cells recapitulate CR PCa and exhibit increased oxidant species levels as well as enhanced signaling of proliferation and survival pathways. H2O2 treatment directly enhanced AS cell growth and migration, which was counteracted by antioxidant N-acetyl cysteine (NAC). We further identified p66Shc protein enhances the production of oxidant species which contributes to phenotypic and cell signaling alterations from AS to AI PCa cells. H2O2-treated LNCaP-AS cells had a similar signaling profile to that of LNCaP-AI or p66Shc subclone cells. Conversely, the oxidant species-driven alterations of LNCaP-AI and p66Shc subclone cell signaling is mitigated by p66Shc knockdown. Moreover, LNCaP-AI cells and p66Shc subclones, but not LNCaP-AS cells, develop xenograft tumors with metastatic nodules, correlating with p66Shc protein levels. Together, the data shows that p66Shc enhances oxidant species production that plays a role in promoting PCa progression to the CR stage. [Display omitted] •Prostate cancer cell progression model mimics clinical progression of castration-resistant cancer.•Androgen-independent cells have a higher level of oxidant species than androgen-sensitive cells.•Treatment of androgen-sensitive cells with hydrogen peroxide promotes growth and migration.•p66Shc protein enhances oxidant species production with a castration-resistant signaling profile.•p66Shc protein levels correlate with prostate cancer metastasis in xenograft animal model.