GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon.
GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon.
复制标题
DOI：
10.1158/0008-5472.can-08-4466
复制
发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Ganapathy V
中科院分区：
文献类型：
--
作者：
Thangaraju M;Cresci GA;Liu K;Ananth S;Gnanaprakasam JP;Browning DD;Mellinger JD;Smith SB;Digby GJ;Lambert NA;Prasad PD;Ganapathy V
短链脂肪酸是由膳食纤维细菌发酵在结肠中产生的，可以预防结直肠癌和炎症性肠病。在这些细菌代谢物中，丁酸盐是生物学上最相关的。GPR109A是烟酸盐的g蛋白偶联受体，但识别丁酸盐的亲和力较低。激活受体需要毫摩尔浓度的丁酸盐。虽然结肠内丁酸盐的浓度足以最大限度地激活受体，但没有关于GPR109A在该组织中的表达/功能的报道。在这里，我们发现GPR109A在结肠和肠上皮细胞面向管腔的顶膜中表达，并且该受体识别丁酸盐作为配体。GPR109A在人类结肠癌、肠道/结肠癌小鼠模型和结肠癌细胞系中表达沉默。GPR109A的肿瘤相关沉默直接或间接涉及DNA甲基化。GPR109A在结肠癌细胞中的重新表达可诱导细胞凋亡，但仅在其配体丁酸盐和烟酸盐存在的情况下。丁酸盐是组蛋白去乙酰化酶的抑制剂，但激活结肠癌细胞中GPR109A及其配体诱导的细胞凋亡并不涉及组蛋白去乙酰化的抑制。凋亡过程的主要变化包括Bcl-2、Bcl-xL、cyclin D1的下调和死亡受体通路的上调。此外，GPR109A/丁酸酯可抑制正常、癌结肠癌细胞系及正常小鼠结肠中NF-κB的活化。这些研究表明GPR109A介导细菌发酵产物丁酸盐在结肠中的肿瘤抑制作用。
Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein-coupled receptor for nicotinate, but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Re-expression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include downregulation of Bcl-2, Bcl-xL, and cyclin D1, and upregulation of death receptor pathway. In addition, GPR109A/butyrate suppresses NF-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon.