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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $59.68 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–72.
Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol. 2000;156:1821–5.
Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111:817–22.
Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993;142:1534–43.
Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.
Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.
Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10:683–95.
Peixoto RD, Ho M, Renouf DJ, Lim HJ, Gill S, Ruan JY, et al. Eligibility of metastatic pancreatic cancer patients for first-line palliative intent nab-paclitaxel plus gemcitabine versus FOLFIRINOX. Am J Clin Oncol. 2017;40:507–11.
Vaccaro V, Sperduti I, Milella M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;365:768–9. Author reply 769.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.
Falasca M, Kim M, Casari I. Pancreatic cancer: current research and future directions. Biochim Biophys Acta. 2016;1865:123–32.
Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun. 2007;362:928–34.
Romero-Zerbo SY, Rafacho A, Diaz-Arteaga A, Suarez J, Quesada I, Imbernon M, et al. A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans. J Endocrinol. 2011;211:177–85.
Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, et al. Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis. PLoS ONE. 2013;8:e76907.
Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem. 2007;282:14056–64.
He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–4.
Vogt M, Munding J, Gruner M, Liffers ST, Verdoodt B, Hauk J, et al. Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch. 2011;458:313–22.
Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–81.
Zheng C, Jiao X, Jiang Y, Sun S. ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J Int Med Res. 2013;41:300–6.
Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 2004;64:3761–6.
Bergman AM, Eijk PP, Ruiz van Haperen VW, Smid K, Veerman G, Hubeek I, et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res. 2005;65:9510–6.
Pineiro R, Maffucci T, Falasca M. The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene. 2011;30:142–52.
Ross RA. L-α-Lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci. 2011;32:265–9.
Falasca M, Corda D. Elevated levels and mitogenic activity of lysophosphatidylinositol in k-ras-transformed epithelial cells. Eur J Biochem. 1994;221:383–9.
Falasca M, Iurisci C, Carvelli A, Sacchetti A, Corda D. Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation. Oncogene. 1998;16:2357–65.
Falasca M, Silletta MG, Carvelli A, Di Francesco AL, Fusco A, Ramakrishna V, et al. Signalling pathways involved in the mitogenic action of lysophosphatidylinositol. Oncogene. 1995;10:2113–24.
Ford LA, Roelofs AJ, Anavi-Goffer S, Mowat L, Simpson DG, Irving AJ, et al. A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol. 2010;160:762–71.
Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, et al. The GPR 55 agonist, L-alpha-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol. 2015;172:4107–18.
Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC Jr., LaPolla JP, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomark Prev. 2004;13:1185–91.
Kargl J, Andersen L, Hasenohrl C, Feuersinger D, Stancic A, Fauland A, et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016;173:142–54.
Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene. 2011;30:245–52.
Perez-Gomez E, Andradas C, Flores JM, Quintanilla M, Paramio JM, Guzman M, et al. The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas. Oncogene. 2013;32:2534–42.
Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-Garcia A, et al. Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget. 2016;7:47565–75.
Paul RK, Wnorowski A, Gonzalez-Mariscal I, Nayak SK, Pajak K, Moaddel R, et al. (R,R ‘)-4 ‘-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility. Biochem. Pharmacol. 2014;87:547–61.
Ji Q, Hao XB, Zhang M,Tang WH, Meng Y, Li L, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE 2009;4:e6816.
Suresh K. An overview of randomization techniques: An unbiased assessment of outcome in clinical research. J Hum Reprod Sci. 2011;4:8–11.
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.
About this article
Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy
ACS Omega (2019)
Journal of Experimental & Clinical Cancer Research (2019)
Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential
Advances in Biological Regulation (2019)
Advances in Biological Regulation (2019)
Journal of Pancreatic Cancer (2019)