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 language | English (US) |
|---|---|
| Pages (from-to) | 2826-2832 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2009 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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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; Gnanaprakasam, Jaya P.; 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 journal › Article
}
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 - Gnanaprakasam, Jaya P.
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
C2 - 19276343
AN - SCOPUS:66149084058
VL - 69
SP - 2826
EP - 2832
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -