Aim:Lactate can signal through the endogenous lactate receptor,GPR81,which is expressed in some cancers.Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition(EMT).This ...Aim:Lactate can signal through the endogenous lactate receptor,GPR81,which is expressed in some cancers.Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition(EMT).This study examined the expression and function of GPR81 in breast cancer samples,and in receptor-positive epithelial vs.triple-negative post-EMT mesenchymal breast cancer cells.Methods:GPR81 mRNA expression was examined by breast cancer microarray,and by a Kaplan-Meier survival curve.Using 3-dimensional culture conditions,GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR.GPR81 siRNA was used to assess the role of GPR81,alone or in conjunction with tamoxifen,in the regulation of MCT1 and MCT4 lactate transporters,intracellular lactate,and cell proliferation and survival.Results:GPR81 mRNA levels were elevated in receptor-positive breast cancer,relative to non-tumor and triple-negative samples,and correlated with increased survival.GPR81 expression was elevated in the two epithelial breast cancer cell lines vs.the corresponding post-EMT mesenchymal cell lines.GPR81 knock-down in epithelial MCF7 cells caused:1,selectively lower mRNA and protein expression of the MCT1 transporter,but not MCT2 or MCT4 ;transporters;2,lower levels of intracellular lactate;and 3,decreased proliferation and survival in lactate only-containing conditions.GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.Conclusion:GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use.As such,GPR81 represents a potential target for treatment of hormone-positive breast cancer cells,and may be prognostic for higher grade breast cancer.展开更多
基金the Fund for Biology from the Cell Biology Department at the University of Connecticut Health Center
文摘Aim:Lactate can signal through the endogenous lactate receptor,GPR81,which is expressed in some cancers.Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition(EMT).This study examined the expression and function of GPR81 in breast cancer samples,and in receptor-positive epithelial vs.triple-negative post-EMT mesenchymal breast cancer cells.Methods:GPR81 mRNA expression was examined by breast cancer microarray,and by a Kaplan-Meier survival curve.Using 3-dimensional culture conditions,GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR.GPR81 siRNA was used to assess the role of GPR81,alone or in conjunction with tamoxifen,in the regulation of MCT1 and MCT4 lactate transporters,intracellular lactate,and cell proliferation and survival.Results:GPR81 mRNA levels were elevated in receptor-positive breast cancer,relative to non-tumor and triple-negative samples,and correlated with increased survival.GPR81 expression was elevated in the two epithelial breast cancer cell lines vs.the corresponding post-EMT mesenchymal cell lines.GPR81 knock-down in epithelial MCF7 cells caused:1,selectively lower mRNA and protein expression of the MCT1 transporter,but not MCT2 or MCT4 ;transporters;2,lower levels of intracellular lactate;and 3,decreased proliferation and survival in lactate only-containing conditions.GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.Conclusion:GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use.As such,GPR81 represents a potential target for treatment of hormone-positive breast cancer cells,and may be prognostic for higher grade breast cancer.
