Expression of pH-Sensitive GPCRs in Peritoneal Carcinomatosis of Colorectal Cancer—First Results

Solid tumors have an altered metabolism with a so-called inside-out pH gradient (decreased pHe < increased pHi). This also signals back to tumor cells via proton-sensitive ion channels or G protein-coupled receptors (pH-GPCRs) to alter migration and proliferation. Nothing, however, is known about the expression of pH-GPCRs in the rare form of peritoneal carcinomatosis. Paraffin-embedded tissue samples of a series of 10 patients with peritoneal carcinomatosis of colorectal (including appendix) origin were used for immunohistochemistry to study the expression of GPR4, GPR65, GPR68, GPR132, and GPR151. GPR4 was just expressed weakly in 30% of samples and expression was significantly reduced as compared to GPR56, GPR132, and GPR151. Furthermore, GPR68 was only expressed in 60% of tumors and showed significantly reduced expression as compared to GPR65 and GPR151. This is the first study on pH-GPCRs in peritoneal carcinomatosis, which shows lower expression of GPR4 and GPR68 as compared to other pH-GPCRs in this type of cancer. It may give rise to future therapies targeting either the TME or these GPCRs directly.

[1]  T. Ettl,et al.  Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors , 2021, Cells.

[2]  Li V. Yang,et al.  GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models. , 2021, Biochimica et biophysica acta. Molecular basis of disease.

[3]  S. Schreml,et al.  Expression profiles of proton-sensing G-protein coupled receptors in common skin tumors , 2020, Scientific Reports.

[4]  N. Heintz,et al.  The habenular G-protein–coupled receptor 151 regulates synaptic plasticity and nicotine intake , 2020, Proceedings of the National Academy of Sciences.

[5]  S. Schulz,et al.  Comprehensive Assessment of GPR68 Expression in Normal and Neoplastic Human Tissues Using a Novel Rabbit Monoclonal Antibody , 2019, International journal of molecular sciences.

[6]  S. Takeda,et al.  GPR31 and GPR151 are activated under acidic conditions. , 2019, Journal of biochemistry.

[7]  P. Insel,et al.  GPR68: An Emerging Drug Target in Cancer , 2019, International journal of molecular sciences.

[8]  Jiancong Hu,et al.  Overexpression of G protein-coupled receptor 31 as a poor prognosticator in human colorectal cancer , 2018, World journal of gastroenterology.

[9]  Meizhu Chen,et al.  Down-regulation of lncTCF7 inhibits cell migration and invasion in colorectal cancer via inhibiting TCF7 expression , 2018, Human Cell.

[10]  Shan Wang,et al.  Long non-coding RNA GPR65-1 is up-regulated in gastric cancer and promotes tumor growth through the PTEN-AKT-slug signaling pathway , 2018, Cell cycle.

[11]  Juxiang Chen,et al.  Overexpression of G-protein-coupled receptors 65 in glioblastoma predicts poor patient prognosis , 2018, Clinical Neurology and Neurosurgery.

[12]  J. Sicklick,et al.  GPR68, a proton‐sensing GPCR, mediates interaction of cancer‐associated fibroblasts and cancer cells , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  Buu P. Tu,et al.  Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets , 2017, Oncotarget.

[14]  M. Kreutz,et al.  Proton‐sensing G protein‐coupled receptors as regulators of cell proliferation and migration during tumor growth and wound healing , 2017, Experimental dermatology.

[15]  A. Saghatelian,et al.  Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis , 2017, Proceedings of the National Academy of Sciences.

[16]  A. Bhatt,et al.  Role of interleukin-6 in cancer progression and therapeutic resistance , 2016, Tumor Biology.

[17]  Wenlian Zhang,et al.  12‐HETER1/GPR31, a high‐affinity 12(S)‐hydroxyeicosatetraenoic acid receptor, is significantly up‐regulated in prostate cancer and plays a critical role in prostate cancer progression , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  C. Thompson,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[19]  N. Lu,et al.  Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor , 2015, Oncotarget.

[20]  Robert J. Gillies,et al.  pH sensing and regulation in cancer , 2013, Front. Physiol..

[21]  Li V. Yang,et al.  Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis , 2013, PloS one.

[22]  Li V. Yang,et al.  Inhibition of tumor cell migration and metastasis by the proton-sensing GPR4 receptor. , 2011, Cancer letters.

[23]  T. Nakakura,et al.  Involvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophages. , 2011, Biochemical and biophysical research communications.

[24]  Li V. Yang,et al.  Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway , 2011, PloS one.

[25]  E. Billy,et al.  Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor , 2011, Angiogenesis.

[26]  Stephen P. H. Alexander,et al.  Guide to Receptors and Channels (GRAC), 5th edition , 2011, British journal of pharmacology.

[27]  Claudiu T. Supuran,et al.  Interfering with pH regulation in tumours as a therapeutic strategy , 2011, Nature Reviews Drug Discovery.

[28]  Matthew P. Jacobson,et al.  Dysregulated pH: a perfect storm for cancer progression , 2011, Nature Reviews Cancer.

[29]  Juan Ren,et al.  Effects of ovarian cancer G protein coupled receptor 1 on the proliferation, migration, and adhesion of human ovarian cancer cells. , 2011, Chinese medical journal.

[30]  H. Aburatani,et al.  The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor , 2010, Proceedings of the National Academy of Sciences.

[31]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[32]  T. Ishizuka,et al.  Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages1 , 2009, The Journal of Immunology.

[33]  Ying Jiang,et al.  Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer. , 2007, Journal of the National Cancer Institute.

[34]  Li V. Yang,et al.  Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH Sensor , 2006, Molecular and Cellular Biology.

[35]  Koichi Sato,et al.  Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: a novel type of multi-functional receptors. , 2005, Cellular signalling.

[36]  R. Cardone,et al.  The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis , 2005, Nature Reviews Cancer.

[37]  C. Distelhorst,et al.  The Glucocorticoid-induced Gene tdag8 Encodes a Pro-apoptotic G Protein-coupled Receptor Whose Activation Promotes Glucocorticoid-induced Apoptosis* , 2004, Journal of Biological Chemistry.

[38]  Romain M. Wolf,et al.  Proton-sensing G-protein-coupled receptors , 2003, Nature.

[39]  M. L. Beau,et al.  A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. , 1998, Proceedings of the National Academy of Sciences of the United States of America.