GROWTH-REGULATORY EFFECT OF GASTRIN ON HUMAN COLON-CANCER CELL-LINES IS DETERMINED BY PROTEIN-KINASE A ISOFORM CONTENT

Cell growth is regulated by various peptide growth factors through receptor-linked multiple intracellular signal-transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP activates cAMP-dependent protein kinase A (PKA) either to stimulate or inhibit cell growth. The effect on growth is determined by the presence of two isoforms of the regulatory (R) subunit of PKA; activation of R(I alpha)-type PKA leads to stimulation of growth, activation of R(II beta)-type inhibits cell growth. We determined whether the effect of gastrin on the growth of human colon cancer cells is determined by cell-specific content of PKA. We utilized two human colon cancer cell lines: LoVo, growth of which is stimulated by gastrin, and HCT116, growth of which is inhibited by gastrin. Activation of both types of PKA with 8-Br-cAMP mimicked the regulation of growth by gastrin; preferential activation of R(II beta)-type PKA with 8-Cl-cArMP inhibited growth of both cell lines. LoVo cells possess the predominantly R(I alpha) isoform of PKA at the mRNA and protein level, HCT116 cells possess predominantly the R(II beta)type PKA. The cAMP-mediated regulation of growth (either stimulatory or inhibitory) by gastrin on these human colon cancer cells was determined by the predominant isoform of PKA.