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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (22), p.6215-6225
• Main Authors: Teng, Yong, Zhao, Huakan, Gao, Lixia, Zhang, Wenfa, Shull, Austin Y, Shay, Chloe
• Format: Article
• Language: English
• Subjects: Activating transcription factor 4; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell culture; Cell Line; Cell Line, Tumor; Cell survival; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Fibroblast growth factor receptor 4; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Gene Expression Regulation, Neoplastic; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - metabolism; Growth factors; Hep G2 Cells; Hepatocellular carcinoma; Humans; Kinases; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice, Inbred BALB C; Mice, Nude; NF-E2-Related Factor 2 - metabolism; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Signal Transduction; Stress; Transcription factors; Transplantation, Heterologous; Tumor cells; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-2039

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-3β (GSK3β) 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-GSK3β-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. .