Histone deacetylase inhibitor trichostatin A resensitizes gemcitabine resistant urothelial carcinoma cells via suppression of TG-interacting factor
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China)
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
- Department of Pathology, Kuo General Hospital, Tainan 701, Taiwan (China)
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
- Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
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 UC were explored. Specimens of 23 locally advanced/advanced stage UTUC patients who received GC systemic chemotherapy after radical nephroureterectomy 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 subline, NGR cells. Our results show that increased TGIF is significantly associated with chemo-resistance, poor progression-free survival, and higher cancer-related deaths of UTUC patients. Higher increases of TGIF, p-AKT{sup Ser473} and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKT{sup Ser473} activation, enhanced migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKT{sup Ser473} activation, declined migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) inhibited TGIF, p-AKT{sup Ser473} expression and migration ability. Synergistic effects of gemcitabine and TSA on NGR cells were also demonstrated. Collectively, TGIF contributes to the gemcitabine resistance of UC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC. - Highlights: • TGIF expression in UC cells is associated with chemoresistance to gemcitabine. • TGIF-regulated AKT activation contributes to the gemcitabine resistance. • Increased TGIF is significantly correlated with chemoresistance of UTUC patients. • TSA counteracted gemcitabine resistance in UC cells by diminishing TGIF expression.
- OSTI ID:
- 22687872
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 290; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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