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 RI alpha-type PKA leads to stimulation of growth, activation of RII 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 RII beta-type PKA with 8-Cl-cAMP inhibited growth of both cell lines. LoVo cells possess the predominantly RI alpha isoform of PKA at the mRNA and protein level; HCT116 cells possess predominantly the RII 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.
Bold
R J
RJ
Department of Surgery, University of Texas Medical Branch, Galveston 77555-0533.
Alpard
S
S
Ishizuka
J
J
Townsend
C M
CM
Thompson
J C
JC
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D005755:Gastrins; D007527:Isoenzymes; C517834:PRKAR1A protein, human; C517837:PRKAR2B protein, human; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases