G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

Abstract

G protein‐coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein‐mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.

Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

“…Although multiple GPCRs are implicated in driving breast cancer formation and progression, the mechanisms underlying GPCR alteration in cancer are largely unknown (32). Moreover, to date, no approaches have effectively targeted multiple GPCRs as a cancer therapeutic (7,11). Our studies show why this has been so difficult: in breast cancer cells, expression of a multiplicity of GPCRs is altered, a finding consistent with reports that various tumor types differentially express more than 50 GPCRs (8).…”

The Role of Serotonin in Breast Cancer Stem Cells

“…Mutations in GPCR that render them ligand-independent have also been identified by DNA sequencing of human tumor samples [ 41 , 42 ]. In fact, approximately 20% of human tumors possess mutated GPCRs or Gα subunits, which mediate signal transduction via cyclic AMP (cAMP).…”

“…In fact, approximately 20% of human tumors possess mutated GPCRs or Gα subunits, which mediate signal transduction via cyclic AMP (cAMP). Moreover, increased copy number alterations and increased expression of genes encoding a subset of 5-HTRs, Gα subunits [ 41 , 42 ], and SERT [ 43 ] have been identified in breast and other tumors. The fact that 5-HTRs and their downstream effectors have been implicated in different cancers raises the prospect that their antagonists may be candidates for anticancer drug development [ 44 , 45 ].…”

Strategies towards Targeting Gαi/s Proteins: Scanning of Protein‐Protein Interaction Sites To Overcome Inaccessibility

“…GPCRs are targeted for numerous diseases, including Alzheimer's disease and cancer. In particular, oncogenic mutations of GPCRs and G proteins have been identified in a significant number of tumors [4,7–10] . As randomly mutated GPCRs can occur, it is difficult to develop drugs that respond to each of these mutations.…”

“…Furthermore, multiple GPCR signaling pathways may be involved in multifactorial diseases, such as asthma or cancer, making it unsuitable to address the GPCRs individually [1,2,11] . Therefore, targeting the downstream G proteins may be an appropriate alternative, further strengthened by the fact that overexpression, abnormal activation, mutations, and dysregulation of G proteins are attributed with diseases such as cancer (Figure 1B, C) [7,8,10] . Besides cancer, G proteins are also associated with cardiovascular diseases, for example, heart failure, diabetes, and chronic inflammatory diseases like asthma [1,12,13] …”