Cell surface lactate receptor GPR81 is crucial for cancer cell survival

Christina L. Roland, Thiruvengadam Arumugam, Defeng Deng, Shi He Liu, Bincy Philip, Sobeyda Gomez, William R. Burns, Vijaya Ramachandran, Huamin Wang, Zobeida Cruz-Monserrate, Craig D. Logsdon

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5301-5310
Number of pages10
JournalCancer Research
Volume74
Issue number18
DOIs
StatePublished - Jun 13 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Roland, C. L., Arumugam, T., Deng, D., Liu, S. H., Philip, B., Gomez, S., Burns, W. R., Ramachandran, V., Wang, H., Cruz-Monserrate, Z., & Logsdon, C. D. (2014). Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Research, 74(18), 5301-5310. https://doi.org/10.1158/0008-5472.CAN-14-0319