FGF21 increases the sensitivity of sorafenib to hepatocellular carcinoma under hypoxia

Abstract

Background: Hepatocellular carcinoma (HCC) is a common disease in human history and one of the main causes of cancer-related death. Insufficient oxygen supply in the tumor microenvironment forces cancer cells to survive in a mild hypoxia environment. Fibroblast growth factor 21 (FGF21), a member of the FGF family, has become the focus of public attention due to its outstanding achievements in diabetes and lipid lowering. However, the mechanism of FGF21 in HCC remains unclear.

Objective: The aims of this study were to clarify whether or not FGF21 could increase the sensitivity of sorafenib (SORA) to HCC under hypoxia and explore the possible mechanism.

Methods: In this study, by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test, plate clone formation test, western blot analysis, Hoechst/propidium iodide double staining experiment, flow cytometry, quantitative reverse transcription polymerase chain reaction, and subcutaneous tumor transplantation in mice, we studied the effects of recombinant human FGF21 combined with SORA on hepatoma cells in vitro and in vivo. FGF21 could enhance the phosphorylation of mothers against decapentaplegic homolog 3 (Smad3) under anaerobic conditions. When combined with SORA, FGF21 could increase the sensitivity of hepatoma cells to SORA and inhibit the growth and migration of hepatoma cells.

Results: FGF21 may increase the sensitivity of HCC to SORA by enhancing the phosphorylation of Smad3 through the phosphatidylinositol 3-kinase/protein kinase B pathway under hypoxia.

Conclusion: Our study suggested the possibility of combination therapy for SORA and FGF21 on HCC.

Keywords

FGF21 / sorafenib / drug resistance / hypoxia / Smad3

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2024 2024 The Authors. Malignancy Spectrum published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.