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 rec eptor-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 c ell 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)-ty pe inhibits cell growth. We determined whether the effect of gastrin o n the growth of human colon cancer cells is determined by cell-specifi c 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-cA MP mimicked the regulation of growth by gastrin; preferential activati on of R(II beta)-type PKA with 8-Cl-cArMP inhibited growth of both cel l lines. LoVo cells possess the predominantly R(I alpha) isoform of PK A at the mRNA and protein level, HCT116 cells possess predominantly th e R(II beta)type PKA. The cAMP-mediated regulation of growth (either s timulatory or inhibitory) by gastrin on these human colon cancer cells was determined by the predominant isoform of PKA.