Online citations, reference lists, and bibliographies.
← Back to Search

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
Referenced 1 time by Citationsy Users

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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
10.1016/j.bbcan.2016.01.001
Pancreatic cancer: Current research and future directions.
M. Falasca (2016)
10.1158/0008-5472.CAN-03-3363
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)
10.1111/j.1476-5381.2010.00743.x
A role for L‐α‐lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells
L. Ford (2010)
10.1158/0008-5472.CAN-05-0989
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)
10.1016/j.tips.2011.01.005
L-α-lysophosphatidylinositol meets GPR55: a deadly relationship.
R. Ross (2011)
10.1097/COC.0000000000000193
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)
10.1038/nature05939
A microRNA component of the p53 tumour suppressor network
Lin He (2007)
10.1038/nrc2899
KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma
J. P. Morris (2010)
10.1038/onc.2012.278
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)
10.1016/S1535-6108(03)00309-X
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.
S. Hingorani (2003)
10.1371/journal.pone.0006816
MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells
Q. Ji (2009)
10.1371/journal.pone.0076907
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)
10.1038/bjc.2014.215
Oncogenic KRAS signalling in pancreatic cancer
S. Eser (2014)
10.1007/s00428-010-1030-5
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)
10.1016/j.bcp.2013.11.020
(R,R')-4'-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility.
R. Paul (2014)
10.1124/PR.58.3.10
Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies
T. Chou (2006)
10.1038/sj.onc.1201758
Release of the mitogen lysophosphatidylinositol from H-Ras-transformed fibroblasts; a possible mechanism of autocrine control of cell proliferation
M. Falasca (1998)
10.1038/onc.2010.402
The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK
C. Andradas (2011)
10.1016/J.BBRC.2007.08.078
Identification of GPR55 as a lysophosphatidylinositol receptor.
S. Oka (2007)
10.1016/S0002-9440(10)65054-7
Genetic progression in the pancreatic ducts.
R. Hruban (2000)
10.1530/JOE-11-0166
A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans.
S. Y. Romero-Zerbo (2011)
10.1038/onc.2010.417
The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation
R. Piñeiro (2011)
10.1016/J.CCR.2005.04.023
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.
S. Hingorani (2005)
10.1111/bph.13196
The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis
N. Hofmann (2015)
10.1111/bph.13345
GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis
J. Kargl (2016)
10.1111/J.1432-1033.1994.TB18750.X
Elevated levels and mitogenic activity of lysophosphatidylinositol in k-ras-transformed epithelial cells.
M. Falasca (1994)
10.18632/oncotarget.10206
Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer
C. Andradas (2016)
10.1177/0300060512474128
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)
10.1016/J.YSUR.2011.08.015
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
K. Behrns (2012)
10.1016/S0140-6736(10)62307-0
Pancreatic cancer
A. Vincent (2011)
10.4103/0974-1208.82352
An overview of randomization techniques: An unbiased assessment of outcome in clinical research
K. Suresh (2011)
10.1074/jbc.M700906200
RAS/ERK Signaling Promotes Site-specific Ribosomal Protein S6 Phosphorylation via RSK and Stimulates Cap-dependent Translation*
Philippe P Roux (2007)



This paper is referenced by
10.1111/febs.14778
Serine/arginine protein‐specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53
G. Wang (2019)
10.3390/cancers12102774
Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines
M. Luongo (2020)
10.3390/molecules25184078
Industrial Hemp (Cannabis sativa subsp. sativa) as an Emerging Source for Value-Added Functional Food Ingredients and Nutraceuticals
H. V. Rupasinghe (2020)
10.3390/cancers12082022
Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy
Aikaterini Emmanouilidi (2020)
10.1038/s41419-020-02892-1
Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts
T. Lowin (2020)
10.1007/978-3-030-50621-6
Druggable Lipid Signaling Pathways
Y. Kihara (2020)
10.1007/s00482-019-00438-9
Cannabidiol bei Tumorerkrankungen
R. Likar (2020)
10.1038/s41419-019-2001-7
Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer
Soyeon Jeong (2019)
10.3390/cancers12041033
Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer
Farjana Afrin (2020)
10.2217/nnm-2019-0063
A GPC1-targeted and gemcitabine-loaded biocompatible nanoplatform for pancreatic cancer multimodal imaging and therapy.
Wenli Qiu (2019)
10.1016/j.ejmech.2020.112163
Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer's disease.
H. Li (2020)
10.1007/978-3-030-50621-6_7
Druggable Lysophospholipid Signaling Pathways.
Keisuke Yanagida (2020)
10.21037/tcr.2019.12.45
Overexpression of lncRNA H19 leads to reduced proliferation in TSCC cells through miR-675-5p/GPR55
Z. Piao (2020)
10.3390/cancers13010157
The Role of Cannabinoids as Anticancer Agents in Pediatric Oncology
Clara Andradas (2021)
10.1016/j.jbior.2019.04.004
ABCC3 is a novel target for the treatment of pancreatic cancer.
A. Adamska (2019)
10.1016/j.jbior.2019.02.001
Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential.
A. Domenichini (2019)
10.1186/s13046-019-1308-7
Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer
A. Adamska (2019)
10.1016/j.bbrc.2020.09.123
Modulation of G-protein-coupled receptor 55-mediated signaling by regulator of G-protein signaling 2.
H. Jang (2020)
10.1016/j.neuroscience.2019.06.039
GPR55-mediated effects on brain microvascular endothelial cells and the blood–brain barrier
L. Leo (2019)
10.3390/cancers12113096
Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management
Valerie Jentzsch (2020)
10.3390/ijms21218035
Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway
Yang Yang (2020)
10.3390/cancers12113203
Cannabidiol (CBD) as a Promising Anti-Cancer Drug
Emily S Seltzer (2020)
10.1016/j.tips.2020.10.001
Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype.
A. C. Cornwell (2020)
10.3748/wjg.v26.i12.1242
Roles of G protein-coupled receptors in inflammatory bowel disease
Z. Zeng (2020)
10.1089/pancan.2018.0019
Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer
G. Sharafi (2019)
10.3390/ph13080174
Receptors and Channels Possibly Mediating the Effects of Phytocannabinoids on Seizures and Epilepsy
Lara Senn (2020)
10.1159/000496356
GPR55-Mediated Effects in Colon Cancer Cell Lines
C. Hasenoehrl (2019)
10.3897/pharmacia.67.e51304
The pharmacological basis for application of cannabidiol in cancer chemotherapy
M. Zhelyazkova (2020)
10.1007/s00482-019-00438-9
[Cannabidiol in cancer treatment].
R. Likar (2020)
Semantic Scholar Logo Some data provided by SemanticScholar