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Cell surface lactate receptor GPR81 is crucial for cancer cell survival.

ABSTRACT: The mechanisms that allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical, and pancreatic carcinoma cell lines. Examination of tumors resected from patients with pancreatic cancer indicated that 94% (148 of 158) expressed high levels of GPR81. Functionally, we observed that the reduction of GPR81 levels using shRNA-mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate. We also observed that lactate addition to culture media induced the expression of genes involved in lactate metabolism, including monocarboxylase transporters in control, but not in GPR81-silenced cells. In vivo, GPR81 expression levels correlated with the rate of pancreatic cancer tumor growth and metastasis. Cells in which GPR81 was silenced showed a dramatic decrease in growth and metastasis. Implantation of cancer cells in vivo was also observed to lead to greatly elevated levels of GPR81. These data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. Furthermore, lactate transport is important for the survival of cancer cells in the tumor microenvironment. Cancer Res; 74(18); 5301-10. ©2014 AACR.

SUBMITTER: Roland CL

PROVIDER: S-EPMC4167222 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Cell surface lactate receptor GPR81 is crucial for cancer cell survival.

Roland Christina L CL Arumugam Thiruvengadam T Deng Defeng D Liu Shi He SH Philip Bincy B Gomez Sobeyda S Burns William R WR Ramachandran Vijaya V Wang Huamin H Cruz-Monserrate Zobeida Z Logsdon Craig D CD

Cancer research 20140613 18

The mechanisms that allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical, and pancreatic carcinoma cell lines. Examination ...[more]

PMID: 24928781

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Project description:BACKGROUND & AIMS:The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, Gi-protein-coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS:Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-interleukin (IL)1?, NLRP3, and caspase-1 (CASP1); release of IL1?; and activation of nuclear factor-?B (NF-?B) and caspase-1. Small interfering RNAs were used to reduce levels of GPR81 and arrestin ?-2 (ARRB2), and an NF-?B luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharide and D-galactosamine. Acute pancreatitis was induced by administration of lipopolysaccharide and cerulein. Some mice were given intraperitoneal injections of sodium lactate or small interfering RNA against Gpr81. Activation of NF-?B in tissue macrophages was assessed in mice that expressed a reporter transgene. RESULTS:In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NF-?B; release of IL1?; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. The administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NF-?B in macrophages of mice, and, when given after injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS:Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1?, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury.

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Cell surface lactate receptor GPR81 is crucial for cancer cell survival.

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Cell surface lactate receptor GPR81 is crucial for cancer cell survival.

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