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GPR68, a proton sensing GPCR, mediates interaction of pancreatic cancer associated fibroblasts and cancer cells
Author(s) -
Wiley Shu,
Sriram Krishna,
Liang Wenjing,
Chang Sarah,
McCann Thalia,
Nishihara Hiroshi,
French Randall,
Lowy Andrew,
Insel Paul
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.695.2
Subject(s) - pancreatic cancer , desmoplasia , cancer research , cancer cell , cancer , chemistry , microbiology and biotechnology , medicine , biology
Pancreatic ductal adenocarcinoma (PDAC) has a unique tumor microenvironment that is characterized by a dense fibrotic stroma (desmoplasia) that is generated by pancreatic cancer associated fibroblasts (PCAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach we identified GPR68, a proton sensing GPCR, has much higher expression in PCAFs compared to both PFs and PSCs. GPR68 also had increased expression in PDAC tumors compared to normal pancreas and its expression was increased in PSCs by co‐culture with PDAC cells or incubation with TNFα. GPR68 activation in PCAFs enhanced expression of interleukin‐6 (IL‐6) via a cAMP/PKA/CREB signaling pathway and GPR68 knockdown with siRNA diminished IL‐6 production by PCAFs and an enhancement in proliferation of PDAC cells by PCAF conditioned media. Use of the allosteric modulator compound ogerin enhanced pH‐dependent increase in cAMP. Furthermore, a pilot screening of 96 GPCR specific compounds tested with GPR68 overexpressing HEK cells identified five compounds that decrease intracellular cAMP at pH6.4, indicating that they may be inhibitors of GPR68. We conclude that PDAC cells induce expression of GPR68 in PCAF, resulting in increased IL‐6 production by PCAFs and enhanced PDAC cell proliferation. This PCAF‐expressed GPR68 thus contributes to PDAC cell‐PCAF interaction and may be a novel therapeutic target for pancreatic cancer, a type of cancer for which new therapies are an important unmet medical need. Support or Funding Information This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) Therapeutic Training Grant 5T32CA121938, NIH/NCI Research Grants R21 CA189477, R01 CA155620, and Padres Pedal the Cause PTC2017, and by an American Society for Pharmacology and Experimental Therapeutics (ASPET)‐David Lehr Research Award. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .