FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4-GSK3β-Nrf2 Signaling

被引:87
作者
Teng, Yong [1 ,2 ]
Zhao, Huakan [3 ,4 ]
Gao, Lixia [1 ]
Zhang, Wenfa [3 ]
Shull, Austin Y. [5 ]
Shay, Chloe [6 ]
机构
[1] Augusta Univ, Dept Oral Biol, 1120 15th St, Augusta, GA 30912 USA
[2] Augusta Univ, Georgia Canc Ctr, Augusta, GA 30912 USA
[3] Chongqing Univ, Sch Life Sci, Chongqing, Peoples R China
[4] Third Mil Med Univ, Inst Canc, Xinqiao Hosp, Chongqing, Peoples R China
[5] Presbyterian Coll, Dept Biol, Clinton, SC USA
[6] Emory Univ, Emory Childrens Ctr, Atlanta, GA 30322 USA
关键词
PROSTATE-CANCER; ER STRESS; ANTIOXIDANT RESPONSE; TRANSCRIPTION FACTOR; GROWTH; NRF2; PROGRESSION; PROLIFERATION; INFLAMMATION; METABOLISM;
D O I
10.1158/0008-5472.CAN-17-2039
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3 beta (GSK3 beta) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4-GSK3 beta-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. (C) 2017 AACR.
引用
收藏
页码:6215 / 6225
页数:11
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