The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status.
The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti-diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion.
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Shin-Jen
SJ
Lin
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Chang-Yi
CY
Lin
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA; Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Dong-Rong
DR
Yang
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Kouji
K
Izumi
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Emily
E
Yan
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Xiaodan
X
Niu
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Hong-Chiang
HC
Chang
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Hiroshi
H
Miyamoto
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Nancy
N
Wang
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA; Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China. Electronic address: ligonghui1970@hotmail.com.
Gonghui
G
Li
The George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan. Electronic address: chang@urmc.rochester.edu.
Chawnshang
C
Chang
D000483:Alleles; D000818:Animals; D050034:Antidiuretic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D045162:Thiazolidinediones / Q000494:pharmacology*
D050034:Antidiuretic Agents; C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D045162:Thiazolidinediones; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)