Protein kinase A-I alpha subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway

Expression of the RI alpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal g rowth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RI alpha gene expression on ovari an cancer cell growth. We report that RI alpha antisense treatment results in a reduction in RI alpha expression and protein kinase A type I, and inhi bition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF recept or, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimul ated mitogen-activated protein kinase activities were reduced. Protein kina se A type I and EGF receptor levels were also reduced in cells overexpressi ng EGF receptor antisense cDNA. These results suggest that the antisense de pletion of RI alpha leads to blockade of both the serine-threonine kinase a nd the tyrosine kinase signaling pathways resulting in arrest of ovarian ca ncer cell growth.