The emerging roles of G alpha 12/13 proteins on the hallmarks of cancer in solid tumors

G12 proteins comprise a subfamily of G-alpha subunits of heterotrimeric GTP-binding proteins (G proteins) that link specific cell surface G protein-coupled receptors (GPCRs) to downstream signaling molecules and play important roles in human physiology. The G12 subfamily contains two family members: G alpha 12 and G alpha 13 (encoded by the GNA12 and GNA13 genes, respectively) and, as with all G proteins, their activity is regulated by their ability to bind to guanine nucleotides. Increased expression of both G alpha 12 and G alpha 13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, G alpha 12/13 proteins are underappreciated in the field of cancer. As our understanding of G protein involvement in oncogenic signaling has evolved, it has become clear that G alpha 12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of G alpha 12/13 proteins is regulated through a series of transcriptional and post-transcriptional mechanisms, several of which are frequently deregulated in cancer. With the ever-increasing understanding of tumorigenic processes driven by G alpha 12/13 proteins, it is becoming clear that targeting G alpha 12/13 signaling in a context-specific manner could provide a new strategy to improve therapeutic outcomes in a number of solid tumors. In this review, we detail how G alpha 12/13 proteins, which were first discovered as proto-oncogenes, are now known to drive several "classical" hallmarks, and also play important roles in the "emerging" hallmarks, of cancer.