The
cyclic AMP-dependent protein kinase (PKA) exists in two
isoforms, PKA-I (type I) and PKA-II (type II), that contain an identical catalytic (C) subunit but distinct regulatory (R) subunits, RI and RII, respectively. Increased expression of
RIalpha/PKA-I has been shown in human
cancer cell lines, in primary
tumors, in cells after transformation, and in cells upon stimulation of growth. We have shown previously that a single-injection RI, antisense treatment results in a reduction in RIalpha and PKA-I expression and sustained inhibition of human colon
carcinoma growth in athymic mice (M. Nesterova and Y. S. Cho-Chung,
Nat. Med., 1: 528-533, 1995). Growth inhibition accompanied reduction in
RIalpha/PKA-I expression and compensatory increases in RIIbeta
protein and PKA-IIbeta, the RIIbeta-containing
holoenzyme. Here, we report that these in vivo findings are consistent with observations made in
cancer cells in culture. We demonstrate that the antisense depletion of RIalpha in
cancer cells results in increased RIIbeta
protein without increasing the rate of RIIbeta synthesis or RIIbeta
mRNA levels. Pulse-chase experiments revealed a 3-6-fold increase in the half-life of RIIbeta
protein in antisense-treated colon and prostate
carcinoma cells with little or no change in the half-lives of RIalpha, RIIalpha, and Calpha
proteins. Compensation by RIIbeta stabilization may represent a novel biochemical adaptation mechanism of the cell in response to sequence-specific loss of RIalpha expression, which leads to sustained down-regulation of PKA-I activity and inhibition of
tumor growth.