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

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-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. .

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

“…Patients with esophageal reflux may be more likely to suffer an increase in FGF19, and all the factors that induced ER stress may facilitate the upregulation of FGF19 and eventually leads to a vicious circle, since increased FGF19, in turn, will promote tumor progression. This is in accordance with results reported that ER acts as a moving organelle with many important cellular functions [33] and FGF19 was reported to protect hepatocellular carcinoma cells against ER stress [12]. Our study established an FGF19-overproducing model to mimic the more malignant phenotype of FGF19-overexpressed LSQ.…”

“…In patients with hepatocellular carcinoma, high amplification of FGF19 promotes progression and epithelial-mesenchymal transition (EMT) by modulating the GSK3β/β-catenin or STAT3 pathway [8][9][10][11]. FGF19 also protects hepatocellular carcinoma cells against endoplasmic reticulum (ER) stress [12]. Furthermore, FGF19 is critical for the progression of breast cancer [13], prostate cancer [14,15], head and neck squamous cell carcinoma [16] and thyroid cancer [17].…”

Intracellular reduction in ATP levels contributes to CYT997‐induced suppression of metastasis of head and neck squamous carcinoma

“…Intracellular ATP levels were determined by ENLITEN ® ATP Assay System (Promega, Madison, MI). Western blot and wound healing assays were carried out as previously described …”

“…Western blot and wound healing assays were carried out as previously described. 6,10,[13][14][15] 2.4 | Three-dimensional (3D) tumour spheroid invasion assays 3D invasion assays were performed as we previously described. 16 Briefly, 2 × 10 4 cells were incubated overnight to form 3D spheroid in hanging droplet in a well of an inverted round bottom 96-well plate, followed by adding150 μl mixture of Matrigel: DMEM without serum at the ratio 1:1.…”

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

“…FGF19/FGFR4 axis recently becomes a promising target for the treatment of HCC. It has been reported that FGF19/FGFR4 inhibited sorafenib-induced ROS generation and apoptosis [69], and was the upstream of NRF2 [70]. But more studies are needed to demonstrate the potential role of FGF19/FGFR4 in NRF2-mediated anti-ferroptosis.…”