Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion

The cAMP-dependent protein kinase types I (PKA-I) and II (PKA-II), composed of identical catalytic (C) subunits but distinct regulatory (R) subunits (RI versus RII), are expressed in a balance of cell growth and differentiation. Distortion of this balance may underlie tumorigenesis and tumor growth. Here, we used PC3M prostate carcinoma cells as a model to overexpress wild type and mutant R and C subunit genes and examined the effects of differential expression of these genes on tumor growth. Only the RII β and mutant RI α -P (a functional mimic of RII β ) transfectants exhibited growth inhibition in vitro , reverted phenotype, and apoptosis, and inhibited in vivo tumor growth. DNA microarrays demonstrated that RII β and RI α -P overexpression upregulated a cluster of differentiation genes, while downregulating transformation and proliferation signatures. Overexpression of RI α and C α , which upregulated PKA-I, elicited the expression signatures opposite that elicited by RII β overexpression. Total colocalization of C α and RII β seen by confocal microscopy in the RII β cell nucleus supports the opposed genomic regulation demonstrated between C α and RII β cells. Differential expression of PKA R subunits may therefore serve as a tumor-target-based gene therapy for PC3M prostate and other cancers.