Dramatic progress is being made in identifying genes involved in cancer genesis and progression. The regulatory subunits of cAMP-dependent protein kinase A (PKA) exist in two isoforms, RI and RII, forming the type-I and -II isozymes, PKA-I and PKA-II, respectively; these isozymes share an identical catalytic (C) subunit. PKA-I and PKA-II are expressed in a balance of cell growth and differentiation; this balance is, however, distorted in cancer cell lines and tumors. An antisense oligonucleotide targeted against RIa restores the functional balance of PKA-I and PKA-II, causing cancer cells to stop growing and to differentiate. Complementary DNA (cDNA) microarray analysis has shown that antisense depletion of the RIa subunit downregulates the expression of a wide range of genes involved in cell proliferation and transformation while upregulating others involved in growth arrest and differentiation, which restores normal signal transduction signatures in tumors that ultimately undergo regression. Overexpression of wild type and mutant R and C subunit genes in cancer cells via inducible vectors demonstrate that only RII? and RIa-P (a functional mimic of RII?) transfectants exhibit inhibition of cell proliferation, reverted phenotype, and apoptosis, and downregulation of excreted PKA (a tumor marker). These results show that the C subunit of PKA, bound with the RIa regulatory subunit forming the PKA-I holoenzyme, is prone to activation in the cell, causing activation of a wide range of genes favoring cell growth. Conversely, when the C subunit is caged in the PKA-II? holoenzyme complex via binding to the RII? regulatory subunit, C-subunit activation becomes minimal, resulting in tumor cell growth arrest and apoptosis. Abnormal expression of the PKA isozymes may be critically involved in tumorigenesis and progression, and therefore PKA isozyme switching may offer a tumor-target-based gene therapy for cancer.
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