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GPR55 Signalling Promotes Proliferation Of Pancreatic Cancer Cells And Tumour Growth In Mice, And Its Inhibition Increases Effects Of Gemcitabine

R. Ferro, A. Adamska, R. Lattanzio, I. Mavrommati, C. Edling, S. A. Arifin, C. Fyffe, G. Sala, L. Sacchetto, G. Chiorino, V. De Laurenzi, M. Piantelli, O. Sansom, T. Maffucci, M. Falasca
Published 2018 · Biology, Medicine
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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.
This paper references
Pancreatic cancer: Current research and future directions.
M. Falasca (2016)
An Increase in the Expression of Ribonucleotide Reductase Large Subunit 1 Is Associated with Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell Lines
J. D. Davidson (2004)
A role for L‐α‐lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells
L. Ford (2010)
In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant.
A. Bergman (2005)
Lysophospholipids are potential biomarkers of ovarian cancer.
R. Sutphen (2004)
L-α-lysophosphatidylinositol meets GPR55: a deadly relationship.
R. Ross (2011)
Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX
R. D. Peixoto (2017)
Progression model for pancreatic cancer.
R. Hruban (2000)
A microRNA component of the p53 tumour suppressor network
Lin He (2007)
KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma
J. P. Morris (2010)
The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas
E. Pérez-Gómez (2013)
A role for L-alphalysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells
LA Ford (2010)
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.
S. Hingorani (2003)
MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells
Q. Ji (2009)
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
Sofia Sisay (2013)
Pancreatic adenocarcinomas frequently show p53 gene mutations.
A. Scarpa (1993)
Oncogenic KRAS signalling in pancreatic cancer
S. Eser (2014)
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
M. Vogt (2010)
(R,R')-4'-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility.
R. Paul (2014)
Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies
T. Chou (2006)
Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation
M. Falasca (1998)
The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK
C. Andradas (2011)
Identification of GPR55 as a lysophosphatidylinositol receptor.
S. Oka (2007)
Genetic progression in the pancreatic ducts.
R. Hruban (2000)
A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans.
S. Y. Romero-Zerbo (2011)
The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation
R. Piñeiro (2011)
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.
S. Hingorani (2005)
The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis
N. Hofmann (2015)
GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis
J. Kargl (2016)
Elevated levels and mitogenic activity of lysophosphatidylinositol in k-ras-transformed epithelial cells.
M. Falasca (1994)
Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer
C. Andradas (2016)
ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells
Chun-ning Zheng (2013)
Signalling pathways involved in the mitogenic action of lysophosphatidylinositol.
M. Falasca (1995)
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
K. Behrns (2012)
Pancreatic cancer
A. Vincent (2011)
An overview of randomization techniques: An unbiased assessment of outcome in clinical research
K. Suresh (2011)
RAS/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation via RSK and Stimulates Cap-dependent Translation*
Philippe P Roux (2007)

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Wenli Qiu (2019)
Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer's disease.
H. Li (2020)
Druggable Lysophospholipid Signaling Pathways.
Keisuke Yanagida (2020)
Overexpression of lncRNA H19 leads to reduced proliferation in TSCC cells through miR-675-5p/GPR55
Z. Piao (2020)
The Role of Cannabinoids as Anticancer Agents in Pediatric Oncology
Clara Andradas (2021)
ABCC3 is a novel target for the treatment of pancreatic cancer.
A. Adamska (2019)
Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential.
A. Domenichini (2019)
Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer
A. Adamska (2019)
Modulation of G-protein-coupled receptor 55-mediated signaling by regulator of G-protein signaling 2.
H. Jang (2020)
GPR55-mediated effects on brain microvascular endothelial cells and the blood–brain barrier
L. Leo (2019)
Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management
Valerie Jentzsch (2020)
Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway
Yang Yang (2020)
Cannabidiol (CBD) as a Promising Anti-Cancer Drug
Emily S Seltzer (2020)
Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype.
A. C. Cornwell (2020)
Roles of G protein-coupled receptors in inflammatory bowel disease
Z. Zeng (2020)
Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer
G. Sharafi (2019)
Receptors and Channels Possibly Mediating the Effects of Phytocannabinoids on Seizures and Epilepsy
Lara Senn (2020)
GPR55-Mediated Effects in Colon Cancer Cell Lines
C. Hasenoehrl (2019)
The pharmacological basis for application of cannabidiol in cancer chemotherapy
M. Zhelyazkova (2020)
[Cannabidiol in cancer treatment].
R. Likar (2020)
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