G protein-coupled receptors: novel targets for drug discovery in cancer

Abstract

G protein-coupled receptors (GPCRs) belong to a superfamily of cell surface signalling proteins that have a pivotal role in many physiological functions and in multiple diseases, including the development of cancer and cancer metastasis. Current drugs that target GPCRs - many of which have excellent therapeutic benefits - are directed towards only a few GPCR members. Therefore, huge efforts are currently underway to develop new GPCR-based drugs, particularly for cancer. We review recent findings that present unexpected opportunities to interfere with major tumorigenic signals by manipulating GPCR-mediated pathways. We also discuss current data regarding novel GPCR targets that may provide promising opportunities for drug discovery in cancer prevention and treatment.

GPR48 Promotes Multiple Cancer Cell Proliferation via Activation of Wnt Signaling

“…GPCRs could be considered as potential oncogenes. Indeed, some gain-of-function mutations of certain GPCRs could directly result in tumor formation and progression (Lappano et al, 2011;Wu et al, 2012). For instance, activating mutation of luteinizing hormone receptors leads to familiar male precocious puberty, and mutation of thyroid-stimulating hormone causes thyroid adenoma (Parma et al, 1993;Shenker et al, 1993).…”

“…For instance, activating mutation of luteinizing hormone receptors leads to familiar male precocious puberty, and mutation of thyroid-stimulating hormone causes thyroid adenoma (Parma et al, 1993;Shenker et al, 1993). Therefore, understanding of the function of GPCRs in cancer cells may provide a potential therapeutic strategy during the treatment of tumorigenesis (Ho et al, 2009;Lappano et al, 2011).…”

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

“…By functional analysis all these genes were clustered in pathways related to tumor metastasis. Specifically, we found that while GPBAR1 activation reduced the expression of MMP7 and MMP13 genes, the expression of two other metalloproteinases MMP3 and MMP10 was robustly enhanced by all there agonists [31][32][33]. Further on, all three GPBAR1 ligands were effective in inducing the expression of ITGB3 [34], a integrin beta-chain subunit coded by a serotoninrelated gene on chromosome 17, that has been reported to be associated with the risk of several human cancers, including colorectal cancer.…”

SphingomabTM, un anticorps anti-sphingosine 1-phosphate, comme agent anti-hypoxique dans le cancer

“…D'un point de vue mécanistique, l'accumulation de HIF-1 dépendante de la S1P repose sur l'activation de la voie de signalisation Akt (protein kinase B [PKB])/GSK3 (glycogen synthase kinase 3b) connue pour réguler la stabilisation de HIF-1 lors d'une hypoxie [14]. En amont, la voie de signalisation PI3K (inositol 1,4,5-trisphosphate 3-kinase)/Akt peut être induite par tous les récepteurs à S1P [15], suggérant que l'activation de la SphK1 en condition d'hypoxie peut être associée à une signalisation autocrine/paracrine de la S1P extracellulaire sécrétée par les cellules hypoxiques. Nos derniers résultats [16] démontrent que la neutralisation de la S1P extracellulaire, par le Sphingomab TM , diminue de façon significative l'accumulation de HIF-1 en conditions d'hypoxie, dans différentes lignées tumorales humaines (prostate, gliome, poumon).…”