title: Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ, NR1C3) and testicular receptor 4 nuclear receptor (TR4, NR2C2) are two members of the nuclear receptor (NR) superfamily that can be activated by several similar ligands/activators including polyunsaturated fatty acid metabolites, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, as well as some anti-diabetic drugs such as thiazolidinediones (TZDs). However, the consequences of the transactivation of these ligands/activators via these two NRs are different, with at least three distinct phenotypes. First, activation of PPARγ increases insulin sensitivity yet activation of TR4 decreases insulin sensitivity. Second, PPARγ attenuates atherosclerosis but TR4 might increase the risk of atherosclerosis. Third, PPARγ suppresses prostate cancer (PCa) development and TR4 suppresses prostate carcinogenesis yet promotes PCa metastasis. Importantly, the deregulation of either PPARγ or TR4 in PCa alone might then alter the other receptor's influences on PCa progression. Knocking out PPARγ altered the ability of TR4 to promote prostate carcinogenesis and knocking down TR4 also resulted in TZD treatment promoting PCa development, indicating that both PPARγ and TR4 might coordinate with each other to regulate PCa initiation, and the loss of either one of them might switch the other one from a tumor suppressor to a tumor promoter. These results indicate that further and detailed studies of both receptors at the same time in the same cells/organs may help us to better dissect their distinct physiological roles and develop better drug(s) with fewer side effects to battle PPARγ- and TR4-related diseases including tumor and cardiovascular diseases as well as metabolic disorders.
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Shin-Jen
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Eungseok
authors.initials: E
authors.lastname: Kim
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Yei-Tsung
authors.initials: YT
authors.lastname: Chen
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Dong-Rong
authors.initials: DR
authors.lastname: Yang
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: M H Eileen
authors.initials: MH
authors.lastname: Tan
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan.
authors.forename: Eu Leong
authors.initials: EL
authors.lastname: Yong
authors.affiliation: George Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, TaiwanGeorge Whipple Laboratory for Cancer ResearchDepartments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USADepartment of Obstetrics and GynecologyNational University of Singapore, Singapore, SingaporeChawnshang Chang Liver Cancer Center and Department of UrologySir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, ChinaDepartment of Biological SciencesChonnam National University, Youngbong, Buk-Gu, Gwangju 500-757 KoreaCardiovascular Research InstituteNational University Health System and The Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeSex Hormone Research CenterChina Medical University/Hospital, Taichung 404, Taiwan chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism* / Q000517:prevention & control*; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; D047495:PPAR gamma
keywords: molecular genetics; prostate