GPFM 09A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon

Muthusamy Thangaraju, Gail A. Cresci, Kebin Liu, Sudha Ananth, Jaya Pranava Gnana-Prakasam, Darren D Browning, John D. Mellinger, Sylvia B Smith, Gregory J. Digby, Nevin A Lambert, Puttur D Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

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 recog- nizes 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. Reexpression 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 down-regulation of Bcl-2, Bcl-xL, and cyclin Dl and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-KB 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.

Original languageEnglish (US)
Pages (from-to)2826-2832
Number of pages7
JournalCancer Research
Volume69
Issue number7
DOIs
StatePublished - Apr 1 2009

Fingerprint

Butyrates
G-Protein-Coupled Receptors
Fermentation
Colon
Colonic Neoplasms
Neoplasms
Niacin
Ligands
Apoptosis
Intestinal Neoplasms
Cell Line
Death Domain Receptors
Cyclins
Histone Deacetylases
Volatile Fatty Acids
Dietary Fiber
DNA Methylation
Inflammatory Bowel Diseases
Histones
Colorectal Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

GPFM 09A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. / Thangaraju, Muthusamy; Cresci, Gail A.; Liu, Kebin; Ananth, Sudha; Gnana-Prakasam, Jaya Pranava; Browning, Darren D; Mellinger, John D.; Smith, Sylvia B; Digby, Gregory J.; Lambert, Nevin A; Prasad, Puttur D; Ganapathy, Vadivel.

In: Cancer Research, Vol. 69, No. 7, 01.04.2009, p. 2826-2832.

Research output: Contribution to journalArticle

Thangaraju, Muthusamy ; Cresci, Gail A. ; Liu, Kebin ; Ananth, Sudha ; Gnana-Prakasam, Jaya Pranava ; Browning, Darren D ; Mellinger, John D. ; Smith, Sylvia B ; Digby, Gregory J. ; Lambert, Nevin A ; Prasad, Puttur D ; Ganapathy, Vadivel. / GPFM 09A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. In: Cancer Research. 2009 ; Vol. 69, No. 7. pp. 2826-2832.
@article{8ab00b2ccc254b3c93d30a30bac73dfc,
title = "GPFM 09A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon",
abstract = "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 recog- nizes 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. Reexpression 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 down-regulation of Bcl-2, Bcl-xL, and cyclin Dl and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-KB 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.",
author = "Muthusamy Thangaraju and Cresci, {Gail A.} and Kebin Liu and Sudha Ananth and Gnana-Prakasam, {Jaya Pranava} and Browning, {Darren D} and Mellinger, {John D.} and Smith, {Sylvia B} and Digby, {Gregory J.} and Lambert, {Nevin A} and Prasad, {Puttur D} and Vadivel Ganapathy",
year = "2009",
month = "4",
day = "1",
doi = "10.1158/0008-5472.CAN-08-4466",
language = "English (US)",
volume = "69",
pages = "2826--2832",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - GPFM 09A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon

AU - Thangaraju, Muthusamy

AU - Cresci, Gail A.

AU - Liu, Kebin

AU - Ananth, Sudha

AU - Gnana-Prakasam, Jaya Pranava

AU - Browning, Darren D

AU - Mellinger, John D.

AU - Smith, Sylvia B

AU - Digby, Gregory J.

AU - Lambert, Nevin A

AU - Prasad, Puttur D

AU - Ganapathy, Vadivel

PY - 2009/4/1

Y1 - 2009/4/1

N2 - 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 recog- nizes 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. Reexpression 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 down-regulation of Bcl-2, Bcl-xL, and cyclin Dl and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-KB 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.

AB - 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 recog- nizes 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. Reexpression 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 down-regulation of Bcl-2, Bcl-xL, and cyclin Dl and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-KB 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.

UR - http://www.scopus.com/inward/record.url?scp=66149084058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149084058&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-4466

DO - 10.1158/0008-5472.CAN-08-4466

M3 - Article

VL - 69

SP - 2826

EP - 2832

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 7

ER -