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Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases
Su Liu1, Shin-Jen Lin1, Gonghui Li1
1George 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.
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.
Insights
Peroxisome proliferator-activated receptor γ (PPARγ) and testicular receptor 4 (TR4) have opposing effects on insulin sensitivity, atherosclerosis, and prostate cancer. Their coordinated action is crucial for regulating prostate cancer, highlighting potential therapeutic targets.
Area of Science:
- Endocrinology and Molecular Biology
- Cancer Research
- Metabolic Disorders
Background:
- Peroxisome proliferator-activated receptor γ (PPARγ) and testicular receptor 4 (TR4) are nuclear receptors activated by similar ligands, including polyunsaturated fatty acid metabolites and thiazolidinediones (TZDs).
- Despite shared activators, PPARγ and TR4 exhibit distinct physiological consequences, impacting insulin sensitivity, atherosclerosis, and prostate cancer (PCa).
Purpose of the Study:
- To investigate the differential roles and coordinated functions of PPARγ and TR4 in regulating physiological processes and disease development.
- To elucidate the complex interplay between PPARγ and TR4 in the context of prostate cancer progression and metastasis.
Main Methods:
- Comparative analysis of PPARγ and TR4 activation by common ligands.
- Examination of the distinct phenotypes associated with PPARγ and TR4 activation, including insulin sensitivity, atherosclerosis risk, and prostate cancer development/metastasis.
- Investigation of the consequences of PPARγ or TR4 deregulation on the other receptor's function in prostate cancer models.
Main Results:
- PPARγ activation enhances insulin sensitivity and attenuates atherosclerosis, while TR4 activation decreases insulin sensitivity and may increase atherosclerosis risk.
- PPARγ suppresses prostate cancer development, whereas TR4 suppresses carcinogenesis but promotes metastasis.
- Deregulation of either PPARγ or TR4 in prostate cancer alters their respective influences, indicating a critical coordination between them in cancer initiation and progression.
Conclusions:
- PPARγ and TR4 play opposing roles in key physiological processes and diseases, including metabolic disorders, cardiovascular health, and cancer.
- The coordinated action of PPARγ and TR4 is essential for regulating prostate cancer initiation, with the loss of one receptor potentially switching the other's role.
- Simultaneous investigation of PPARγ and TR4 is crucial for understanding their distinct roles and developing targeted therapies with fewer side effects for related diseases.
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