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G‐protein‐coupled receptor for short‐chain fatty acids suppresses colon cancer
Author(s) -
Tang Yong,
Chen Yakun,
Jiang Hongmei,
Robbins Gregory T.,
Nie Daotai
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25638
Subject(s) - butyrate , cancer research , biology , cyclin dependent kinase 6 , cyclin dependent kinase , apoptosis , adenocarcinoma , downregulation and upregulation , cancer , programmed cell death , cell cycle , chemistry , biochemistry , genetics , fermentation , gene
GPR43 is a G‐protein‐coupled receptor for short‐chain fatty acids (SCFAs). Expression of GPR43 is detected in hematopoietic tissues and the large intestine. SCFAs are derived from bacterial fermentation and metabolism of undigested dietary fibers and have been recognized for their cancer prevention activities in the colon. The role of SCFAs, particularly butyrate, in colon cancer therapy has been extensively studied, and its tumor suppressive functions are believed to be due to their intracellular actions, notably inhibition of histone deacetylase. In our study, we show that SCFAs also exert their antitumor effects via receptor GPR43 and that GPR43 is frequently lost in colon cancer cells. Immunohistostaining revealed that GPR43 immunoreactivity was high in normal colon tissues ( N = 31) but was markedly reduced or completely lost in most colorectal adenocarcinoma tissues ( N = 70) and their corresponding lymph node metastatic adenocarcinomas ( N = 38). RT‐PCR analysis detected the presence of full length GPR43 mRNA in only one (HT‐29) of nine established human colon cancer cell lines. Restoration of GPR43 expression in HCT8 human colonic adenocarcinoma cells induced G0/G1 cell cycle arrest and activated caspases, leading to increased apoptotic cell death after propionate/butyrate treatment. Restored GPR43 expression, coupled with propionate treatment, induced an upregulation of p21 and a decrease in the levels of cyclin D3 and cyclin‐dependent kinases (CDKs) 1 and 2, while the CDK4 and CDK6 levels remained unchanged. Our results suggest that GPR43 functions as a tumor suppressor by mediating SCFA‐induced cell proliferation inhibition and apoptotic cell death in colon cancer.