GPR68, a proton sensing GPCR, mediates interaction of pancreatic cancer associated fibroblasts and cancer cells

Abstract

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 InformationThis 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.

Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer

“…The molecular mechanisms by which the extracellular A large amount of evidence shows that the expression level of OGR1 is closely related to tumor proliferation, metastasis, angiogenesis and tumor immunity. i) OGR1 promotes tumor cell proliferation and tumor growth in prostate cancer (Singh et al, 2007), melanoma, colorectal cancer and pancreatic ductal adenocarcinoma (Li et al, 2009;Horman et al, 2017;Wiley et al, 2018;Cao et al, 2021). Moreover, OGR1 mRNA expression is upregulated in many tumors (Wiley et al, 2019).…”

GPR68 inhibited nucleus or ER to exosome non-protein based circadian exercise based on Thalamus big data

“…Such as, GPR68 is also expressed in the nervous system, participating in a variety of physiological and pathological processes [1][2][3][4]. The abnormal expression of GPR68 is related to the occurrence and development of multiple cancer [5][6][7][8][9][10][11][12][13]. The current research mainly focuses on its regulatory mechanism [14][15][16][17][18], signaling pathways [19][20][21][22][23] and potential clinical applications.…”