G-protein-coupled receptor signaling in cancer development and treatment

Division Of Basic Sciences - Nci

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Abstract

The PKA inhibitor (PKI) family members PKIalpha, PKIbeta, and PKIgamma, bind with high affinity to PKA and block its kinase activity, modulating the extent and duration of PKA mediated signaling events. While PKA is a well known regulator of physiological and oncogenic events, the role of PKI proteins in these pathways has remained elusive. I have demonstrated that overexpression of the PKA binding domain of PKIalpha (PKIalpha1 24) in the skin is sufficient to induce BCC formation. My results suggested that expression levels of endogenous PKIs could have a role in mediating tumor formation or suppression by modulating PKA activity. Indeed, analysis of PKI genomic alterations in the TCGA dataset indicated that amplification of the gene coding for PKIalpha (PKIA) is common in various cancers with the greatest frequency in prostate cancer samples. Further analyzing PKIA gene amplifications indicated a correlation with a significant reduction in time to prostate cancer progression. Furthermore, in vitro metastasis assays using prostate cancer cell lines revealed that PKIA supports cell migration and confers resistance to detachment-induced apoptosis (anoikis). Taken together, we hypothesize that PKIA potentiates prostate cancer progression and metastasis. Our ongoing investigations are focused on identifying the molecular mechanisms involved in these prostate cancer phenotypes to better clarify the role of PKIA in potentiating metastasis and tumor growth; potentially revealing novel therapeutic targets in advanced prostate cancer.