A short-chain fatty acid, propionate, enhances the cytotoxic effect of cisplatin by modulating GPR41 signaling pathways in HepG2 cells

Oncotarget
Mamiko KobayashiMasayuki Iwano

Abstract

Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are generated by microbial fermentation of indigestible fiber by gut flora. SCFAs are ligands of two orphan G protein-coupled receptors, GPR41 and GPR43, that modulate cell proliferation and induce apoptosis. However, it is unclear if SCFAs enhance the effects of chemotherapy in a GPR41- or GPR43-dependent manner. The aim of this study was to investigate whether SCFAs, and particularly propionate, activate GPR41 or GPR43, and thereby enhance the antitumor effects of cisplatin in HepG2 human hepatocellular carcinoma (HCC) cells. The inhibitory effects of propionate and cisplatin on proliferation of HCC cells were determined by MTS assay. Changes in apoptosis rate were analyzed by flow cytometry. The effects of combined propionate and cisplatin on these properties in HCC cells were significantly higher than those of cisplatin alone. With combined treatment, the levels of cleaved caspase-3, active caspase-3 forms, and acetylated histone H3 were enhanced in a GPR41-dependent manner; expression of histone deacetylases (HDAC) 3, 4, 5, 6, 8 proteins was significantly reduced; and induction of TNF-α expression was significantly enhanced. These results suggest tha...Continue Reading

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Citations

Oct 30, 2020·Cells·Jesús Cosín-RogerSara Calatayud
Feb 19, 2021·Nutrition Research·Iván López-MéndezVarenka J Barbero-Becerra
Apr 2, 2021·Critical Reviews in Food Science and Nutrition·Gaoxing MaHang Xiao
Nov 19, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Ryan KurtzBlythe D Shepard

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Methods Mentioned

BETA
surgical resection
acetylation
FACS
ELISA
xenografts
xenograft
Assay
PCR
transfection
flow cytometry

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Apoptosis

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