title: Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.
abstract: Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Department of Urology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China.
authors.forename: Dong-Rong
authors.initials: DR
authors.lastname: Yang
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Department of Urology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 310016 China.
authors.forename: Xian-Fan
authors.initials: XF
authors.lastname: Ding
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Urology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China.
authors.forename: Yu-Xi
authors.initials: YX
authors.lastname: Shan
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Ronghao
authors.initials: R
authors.lastname: Wang
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Shin-Jen
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Department of Urology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 310016 China.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Department of Urology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Urology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China. Electronic address: soook_lee@urmc.rochester.edu.
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan. Electronic address: chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006023:Glycoproteins; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D010455:Peptides; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D006023:Glycoproteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; C490515:NR2C2 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D043823:Taxoids; D000077143:Docetaxel; D005047:Etoposide
keywords: Cancer Stem Cells; Chemoresistance; Drug Resistance; Nuclear Receptors; Oct4; Prostate Cancer; Testicular Orphan Nuclear Receptor 4