title: ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling pathway.
abstract: Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression. Interrupting HIF2α/VEGF signals with inhibitors of either HIF2α or VEGF was sufficient to suppress RCC progression. Similarly, the specific AR degradation enhancer ASC-J9 was sufficient to suppress AR-induced HIF2α/VEGF signaling and RCC progression in multiple models in vitro and in vivo. Taken together, our results revealed a novel role for AR in RCC initiation and progression with implications for novel therapeutic strategies.
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. chang@urmc.rochester.edu lilydr@hotmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Luke
authors.initials: L
authors.lastname: Chang
authors.affiliation: George Whipple Lab for Cancer Research, University of Rochester Medical Center, Rochester, New York, New York. Department of Pathology, University of Rochester Medical Center, Rochester, New York, New York. Department of Urology, University of Rochester Medical Center, Rochester, New York, New York. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York, New York. The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, New York.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: George Whipple Lab for Cancer Research, University of Rochester Medical Center, Rochester, New York, New York. Department of Pathology, University of Rochester Medical Center, Rochester, New York, New York. Department of Urology, University of Rochester Medical Center, Rochester, New York, New York. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York, New York. The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, New York.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.affiliation: George Whipple Lab for Cancer Research, University of Rochester Medical Center, Rochester, New York, New York. Department of Pathology, University of Rochester Medical Center, Rochester, New York, New York. Department of Urology, University of Rochester Medical Center, Rochester, New York, New York. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York, New York. The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, New York. Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan. chang@urmc.rochester.edu lilydr@hotmail.com.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003474:Curcumin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C471106:ASC-J9 compound; C467484:VEGFA protein, human