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

Abstract

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 and mutant RI-P (a functional mimic of RII) transfectants exhibited growth inhibition in vitro, reverted phenotype, and apoptosis, and inhibited in vivo tumor growth. DNA microarrays demonstrated that RII and RI-P overexpression upregulated a cluster of differentiation genes, while downregulating transformation and proliferation signatures. Overexpression of RI and C, which upregulated PKA-I, elicited the expression signatures opposite that elicited by RII overexpression. Total colocalization of C and RII seen by confocal microscopy in the RII cell nucleus supports the opposed genomic regulation demonstrated between C and RII cells. Differential expression of PKA R subunits may therefore serve as a tumor-target-based gene therapy for PC3M prostate and other cancers.