title: New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells.
abstract: The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
authors: George Whipple Lab for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642,  USA.
authors: Soo Ok
authors: SO
authors: Lee
authors: Zhifang
authors: Z
authors: Ma
authors: Chiuan-Ren
authors: CR
authors: Yeh
authors: Jie
authors: J
authors: Luo
authors: Tzu-Hua
authors: TH
authors: Lin
authors: Kuo-Pao
authors: KP
authors: Lai
authors: Shinichi
authors: S
authors: Yamashita
authors: Liang
authors: L
authors: Liang
authors: Jing
authors: J
authors: Tian
authors: Lei
authors: L
authors: Li
authors: Qi
authors: Q
authors: Jiang
authors: Chiung-Kuei
authors: CK
authors: Huang
authors: Yuanjie
authors: Y
authors: Niu
authors: Shuyuan
authors: S
authors: Yeh
authors: Chawnshang
authors: C
authors: Chang
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D000077209:Decitabine; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001374:Azacitidine; D003474:Curcumin; D000077209:Decitabine; D011944:Receptors, Androgen; C471106:ASC-J9 compound