The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients’ outcome.
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This work was supported by Pancreatic Cancer Research Fund and Avner Pancreatic Cancer Foundation (grants to MF). RF, CAF, CEE were supported by Pancreatic Cancer Research Fund (grants to MF). AA is supported by Curtin International Postgraduate Research Scholarship (CIPRS)/Health Sciences Faculty International Research Scholarship (HSFIRS). GS was supported by Ministero Sanità Finalizzata 2011/2012. VDL was supported by AIRC IG 15196.c. We thank Prof David A.Tuveson and Prof David Baker for KC/KPC and GPR55−/− mice respectively; Dr Massimo Broggini for p53 mutants constructs; Prof Hemant Kocher for HPDE cells; GW Pharmaceuticals for providing the cannabidiol used in this study; the Pathology Core facility of the Blizard Institute for helping with IHC. AA, VDL and MF also acknowledge the infrastructure and staff support provided by CHIRI, School of Pharmacy & Biomedical Sciences and by Faculty of Health Sciences, Curtin University.
RF and MF designed, coordinated, and carried out the bulk of the experiments. RF, AA, IM, TM and MF performed in vitro experiments. RF, TM, and MF designed and supervised in vitro experiments. RF, GS, and MF designed and supervised in vivo experiments. RF performed in vivo experiments. SAA, CAF, CEE, and VDL contributed to in vivo experiments. RF and RL performed IHC assay. RL and MP performed IHC analysis. LS and GC performed in silico analysis. OJS provided key reagents. RF, TM, and MF wrote the manuscript. MF conceived the project, led and supervised the study.
Conflict of interest
The authors declare that they have no conflict of interest.
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Ferro, R., Adamska, A., Lattanzio, R. et al. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene 37, 6368–6382 (2018). https://doi.org/10.1038/s41388-018-0390-1
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