FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4–GSK3β–Nrf2 signaling

Yong Teng, Huakan Zhao, Lixia Gao, Wenfa Zhang, Austin Y. Shull, Chloe Shay

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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-3b (GSK3b) 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–GSK3b–Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management.

Original languageEnglish (US)
Pages (from-to)6215-6225
Number of pages11
JournalCancer Research
Volume77
Issue number22
DOIs
StatePublished - Nov 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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