TY - JOUR
T1 - Histone deacetylase inhibitor trichostatin A resensitizes gemcitabine resistant urothelial carcinoma cells via suppression of TG-interacting factor
AU - Yeh, Bi Wen
AU - Li, Wei Ming
AU - Li, Ching Chia
AU - Kang, Wan Yi
AU - Huang, Chun Nung
AU - Hour, Tzyh Chyuan
AU - Liu, Zi Miao
AU - Wu, Wen Jeng
AU - Huang, Huei Sheng
N1 - Funding Information:
This work was supported in part by grants from the Ministry of Science and Technology (Taipei, Taiwan; NSC98-2320-B-006-008-MY3 , NSC101-2320-B-006-034 , NSC102-2320-B-006-017 , NSC98-2314-B-037-041-MY3 , NSC101-2314-B-037-007-MY3 ), by a grant from Health and Welfare surcharge of tobacco products, Ministry of Health and Welfare ( MOHW104-TDU-B-212-124-003 ), and is supported partially by Center for Infectious Disease and Cancer Research, Kaohsiung Medical University “Aim for the Top Universities Grant, grant No. KMU-TP103 E19 ”.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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-AKTSer473 and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKTSer473 activation, enhanced migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKTSer473 activation, declined migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) inhibited 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 UC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC.
AB - 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-AKTSer473 and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKTSer473 activation, enhanced migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKTSer473 activation, declined migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) inhibited 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 UC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC.
UR - http://www.scopus.com/inward/record.url?scp=84951569549&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84951569549&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2015.11.007
DO - 10.1016/j.taap.2015.11.007
M3 - Article
C2 - 26589485
AN - SCOPUS:84951569549
SN - 0041-008X
VL - 290
SP - 98
EP - 106
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -
