1高雄醫學大學 泌尿學科；2高雄醫學大學附設中和紀念醫院 泌尿科；3衛生福利部屏東醫院
泌尿科；4高雄市立大同醫院 泌尿科； 5郭綜合醫院 病理科； 6高雄醫學大學 生化學科；
7國立成功大學 生物醫技研究所；8高雄市立小港醫院 泌尿科
Histone deacetylase inhibitor trichostatin A synergistically resensitizes a gemcitabine resistant urothelial carcinoma cells via suppression of TG-interacting factor
and AKT activation
Bi-Wen Yeh1,2, Wei-Ming Li1,2,3, Ching-Chia Li1,2,4, Wan-Yi Kang5, Chun-Nung Huang1,2, Tzyh-Chyuan Hour6, Zi-Miao Liu7, Huei-Sheng Huang7*, Wen-Jeng Wu1,2,8*
1Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan；2Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan; 4Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 5Department of Pathology, Kuo General Hospital, Tainan 701, Taiwan；6 Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan；7 Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan； 8Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
Purpose: Gemcitabine and cisplatin (GC) has been widely used for advanced and metastatic urothelial carcinoma (UC). However, resistance to this remedy has been noticed. We have demonstrated that increase of TG-interacting factor (TGIF) in specimens is associated with worse prognosis of upper tract UC (UTUC) patients. The roles of TGIF in the gemcitabine resistance of UTUC and a promising therapeutic strategy to UC were explored.
Materials and Methods: Specimens of 23 UTUC patients who received GC systemic chemotherapy were collected to evaluate the alterations of TGIF in the resistance to the remedy by using immunohistochemistry. In vitro characterizations of mechanisms mediating TGIF in gemcitabine resistance were conducted by analyzing NTUB1 cells and their gemcitabine-resistant sublines, NGR cells.
Results and conclusions: Increased TGIF and p-AKTSer473 are significantly associated with chemo-resistance, poor progression-free survival, and higher cancer-related deaths of UTUC patients. Higher increases of TGIF, p-AKTSer473, and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKTSer473 activation, migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKTSer473 activation, migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) can inhibit TGIF, p-AKTSer473 expression and migration ability. Synergistic effects of gemcitabine and TSA on NGR cells were also demonstrated. Collectively, TGIF contributes to the gemcitabine resistance of UTUC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC.