Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells

Background: The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in two isoforms, RI and RII, which distinguish the PKA isozymes, type I (PKA-I) and type II (PKA-II). Evidence obtained from a variety of different experimental approaches has shown that the relative levels of type I and type II PKA in cells can play a major role in determining the balance between cell growth and differentiation. In order to characterize the effect of PKA type I and type II regulatory subunits on gene transcription at a global level, the PKA regulatory subunit genes for RI alpha and RII beta were stably transfected into cells of the ovarian cancer cell line (OVCAR8). Results: RI alpha transfected cells exhibit hyper-proliferative growth and RII beta transfected cells revert to a relatively quiescent state. Profiling by microarray revealed equally profound changes in gene expression between RI alpha, RII beta, and parental OVCAR cells. Genes specifically up-regulated in RI alpha cells were highly enriched for pathways involved in cell growth while genes up-regulated in RII beta cells were enriched for pathways involved in differentiation. A large group of genes (similar to 3600) was regulated along an axis of proliferation/differentiation between RI alpha, parental, and RII beta cells. RI alpha/wt and RII beta/wt gene regulation was shown by two separate and distinct gene set analytical methods to be strongly cross-correlated with a generic model of cellular differentiation. Conclusion: Overexpression of PKA regulatory subunits in an ovarian cancer cell line dramatically influences the cell phenotype. The proliferation phenotype is strongly correlated with recently identified clinical biomarkers predictive of poor prognosis in ovarian cancer suggesting a possible pivotal role for PKA regulation in disease progression.