br Declaration of interest br
Declaration of interest
This work was supported by grants from the Polish National Science Centre (PRELUDIUM grant no. 2013/11/N/NZ5/00270) and the European Commission FP7 Project Beta-JUDO (grant number 279 153), European Union EIT Health project DeTecT2D, Swedish Diabetes Association (grant number DIA 2016–146), Family Ernfors Foundation (grant number 170504), EXODIAB, the Swedish Society for Diabetology and the Regional Research Council Uppsala.
Introduction While there have been significant advances in the treatment of cancer, a number of tumors are resistant to frontline chemotherapeutic agents and patients who receive chemotherapy often relapse with the development of multidrug resistance (MDR) , . MDR is a complex interrelated phenomenon, which is dependent, in part, upon increased Estradiol 17-(β-D-Glucuronide) sodium salt mg and function of ABC transporters such as P-glycoprotein (P-gp, MDR1/ABCB1), multidrug resistance protein 17 (MRP1-7, ABCC1-7) and breast cancer resistance protein (BCRP, ABCG2) , . For example, pancreatic adenocarcinoma (PancCa) is the fourth leading cause of cancer death in the U.S. and has one of the worst clinical prognosis as only 6% of PancCa patients will survive beyond 5 years post diagnosis . MDR contributes to the poor response to frontline treatment of PancCA , as enhanced expression of MRP-1, MRP-3 and MRP-5 has been associated with resistance to gemcitabine and 5-fluorouracil . In the treatment of breast cancer, over 80% of the breast cancer patients who receive chemotherapy will relapse with the eventual development of MDR disease primarily associated with overexpression of Pgp, MRP1 and BCRP , . The expression of the MDR phenotype in tumors has been linked to activation of the epidermal growth factor receptor (EGFR) and the subsequent downstream increase in ERK1/2 phosphorylation (p-ERK), which contributes to increased MDR-related protein expression , , . Cellular proliferation and MDR have also been associated with increased expression of β-catenin and hypoxia-inducible factor 1α (HIF-1α) , , . Another key player implicated in the upregulation of genes linked to tumor proliferation is pyruvate kinase M2 (PKM2) , , whose phosphorylation by ERK2 enables its nuclear translocation ,  and association with β-catenin to enhance transactivation of target genes, including cyclin D1 (CCND1) , . Activated Wnt/β-catenin pathway activity has been found to enhance Pgp expression in chronic myeloid leukemia  and cholangiocarcinoma , while the knockdown of β-catenin decreases BCRP expression and augments the antiproliferative effects of 5-fluorouracil in MDA-MB-468 breast cancer cells  and downregulates Pgp expression in glioblastoma stem cells . In response to ERK-mediated phosphorylation, PKM2 binds with nuclear HIF-1α to upregulate HIF-1α-dependent transcription . Notably, HIF-1α transactivates Pgp gene expression in breast, colon, and stomach tumors and raises MRP-2 levels in breast cancer cell lines . However, the contribution of PKM2 to the expression and function of MDR proteins through its association with β-catenin and HIF-1α pathways remains unclear. The relationship between increased activity of the MEK/ERK and PI3K-AKT pathways with oncogenesis and elevated MDR protein expression makes these pathways important targets for drug development. One potential approach is through the inhibition of GPR55, a G protein-coupled receptor whose activation is linked to tumorigenesis via increased activity of the MEK/ERK and PI3K-AKT pathways , , , . Elevated expression of GPR55 mRNA has been linked to aggressiveness in human PancCa and glioblastoma tumors, and GPR55 siRNA knockdown reduced growth of a T98G glioblastoma tumor maintained as a subcutaneous tumor in mice . GPR55 expression was detected in MDA-MB-231 breast cancer cell lines and incubation with the endogenous GPR55 agonist l-α-lysophosphatidylinositol (LPI) increased cellular migration, orientation and polarization . In prostate and ovarian tumor cells, LPI activation of GPR55 increased p-ERK and p-AKT concentrations, which was blocked by pre-incubation with the GPR55 antagonist cannabidiol . In addition, siRNA-mediated GPR55 knockdown and treatment with the GPR55 antagonist CID 16020046 (CID) effectively blocked the LPI-mediated ovarian cancer-induced angiogenesis in an in vivo chicken chorioallantoic assay .