Cancer research · 2018
Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод в очереди
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McClinch Kimberly, Avelar Rita A, Callejas David, Izadmehr Sudeh, Wiredja Danica, Perl Abbey, Sangodkar Jaya, Kastrinsky David B, Schlatzer Daniela, Cooper Maxwell, Kiselar Janna, Stachnik Agnes, Yao Shen, Hoon Divya, McQuaid Daniel, Zaware Nilesh, Gong Yixuan, Brautigan David L, Plymate Stephen R, Sprenger Cynthia C T, Oh William K, Levine Alice C, Kirschenbaum Alexander, Sfakianos John P, Sears Rosalie, DiFeo Analisa, Ioannou Yiannis, Ohlmeyer Michael, Narla Goutham, Galsky Matthew D
Аннотация
Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. Cancer Res; 78(8); 2065-80. ©2018 AACR.