Gα13 Promotes Clonogenic Growth by Increasing Tolerance to Oxidative Metabolic Stress in Prostate Cancer Cells

The oncogenic role of the G12 family in many human solid cancers has been extensively studied, primarily through the effects of constitutively active mutants of these proteins on cell migration and invasion. However, these mutations are not seen in cancers, and the biological role of G alpha 13 in prostate cancer tumorigenesis is largely unexplored. Here, we report that G alpha 13 promotes anchorage-independent colony formation, spheroid formation, and xenograft tumor growth in human prostate cancer cell lines. Transcriptome analyses suggest that G alpha 13 modulates genes in the mitochondria and are involved in the oxidative stress response. Silencing of GNA13 increased mitochondrial superoxide levels when prostate cancer cells were cultured in galactose medium and increased the sensitivity to oxidative metabolic stress when the cells were cultured in media containing non-glycolytic metabolites. Furthermore, G alpha 13 levels impacts the abundance of superoxide dismutase 2 (SOD2) in the mitochondria, as well as SOD2 promoter activity and mRNA expression. Importantly, expression of SOD2 could rescue the effect of G alpha 13 loss on suppression of anchorage-independent growth. Likewise, stable knockdown of SOD2 decreased anchorage-independent cell growth, which was enhanced by overexpression of G alpha 13. These results outline a novel biological function of G alpha 13 mediated via SOD2 in prostate cancer tumorigenesis and highlight it as a potential treatment target.