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: Gα12 and Gα13 (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 Gα12 and Gα13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, Gα12/13 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 Gα12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of Gα12/13 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 Gα12/13 proteins, it is becoming clear that targeting Gα12/13 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 Gα12/13 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.

Edited by Henrik G. Dohlman GNA13, the ␣ subunit of a heterotrimeric G protein, mediates signaling through G-protein-coupled receptors (GPCRs). GNA13 is up-regulated in many solid tumors, including prostate cancer, where it contributes to tumor initiation, drug resistance, and metastasis. To better understand how GNA13 contributes to tumorigenesis and tumor progression, we compared the entire transcriptome of PC3 prostate cancer cells with those cells in which GNA13 expression had been silenced. This analysis revealed that GNA13 levels affected multiple CXC-family chemokines. Further investigation in three different prostate cancer cell lines singled out pro-tumorigenic CXC motif chemokine ligand 5 (CXCL5) as a target of GNA13 signaling. Elevation of GNA13 levels consistently induced CXCL5 RNA and protein expression in all three cell lines. Analysis of the CXCL5 promoter revealed that the ؊505/؉62 region was both highly active and influenced by GNA13, and a single NF-B site within this region of the promoter was critical for GNA13-dependent promoter activity. ChIP experiments revealed that, upon induction of GNA13 expression, occupancy at the CXCL5 promoter was significantly enriched for the p65 component of NF-B. GNA13 knockdown suppressed both p65 phosphorylation and the activity of a specific NF-B reporter, and p65 silencing impaired the GNA13-enhanced expression of CXCL5. Finally, blockade of Rho GTPase activity eliminated the impact of GNA13 on NF-B transcriptional activity and CXCL5 expression. Together, these findings suggest that GNA13 drives CXCL5 expression by transactivating NF-B in a Rho-dependent manner in prostate cancer cells. Prostate cancer is the second most prevalent cancer in males and is currently ranked the 5th leading cause of cancer deaths worldwide (1). The major reasons for death from prostate cancer are metastasis, drug resistance, and tumor relapse (2). As such, identifying the cellular mechanisms that contribute to prostate tumorigenesis and cancer progression would aid in the development of novel therapeutics to improve outcomes (3). Although previous studies on prostate cancer signaling have mostly focused on androgen hormone-signaling pathways, recent investigations have implicated G-protein-coupled receptors (GPCRs) 3 and their downstream signaling molecules in prostate cancer initiation and progression (3, 4). GPCRs are the largest and most diverse group of integral membrane proteins in eukaryotes. These proteins mediate cellular responses to a wide variety of ligands and are also important for numerous physiological functions (5). GPCRs are coupled to heterotrimeric G proteins that are made up of G ␣ , G ␤ , and G ␥ subunits, from which the G ␣ class can be further categorized into the G s , G q , G i , and G 12 subfamilies (6). Heterotrimeric G proteins function as molecular switches; ligand binding to the GPCR triggers a conformational change in the transmembrane region of the receptor, resulting in a GDP-GTP exchange on the G ␣ subunit and its subsequent dissociation from the...