Octreotide differentially modulates human Caco-2 intestinal epithelial cell proliferation and differentiation by decreasing intracellular cAMP.
Somatostatin modulates gastrointestinal mucosal growth and differentiation indirectly via inhibition of bioactive peptides and directly by less well understood mechanisms. We studied the direct effects of the somatostatin analog octreotide on proliferation, brush-border enzyme activity, cell-matrix interactions and intracellular cAMP in Caco-2 human intestinal epithelial cells. Proliferation was assessed by cell counting and [3H]thymidine uptake. The brush-border enzymes alkaline phosphatase (AP) and dipeptidyl dipeptidase (DP) were quantitated by synthetic substrate digestion. Adhesion and migration on purified matrix proteins were also measured. Octreotide (10(-9)-10(-5)M) shortened doubling time (46.5 +/- 6.2% at 10(-5) M, n = 20, P < 0.0001) and stimulated [3H]thymidine uptake. Octreotide decreased intracellular cAMP by 19.4 +/- 5.0% (n = 7, P < 0.0001) while dibutyryl-cAMP (10(-6) M) prolonged doubling time by 10.1 +/- 1.5% (n = 8, P < 0.0001), and blocked the octreotide effect. Octreotide decreased AP and DP with maximal effect at 10(-6) M (36.8 +/- 8.3% and 20.5 +/- 9.1%, n > 7, P < 0.0005 respectively). However, mitomycin proliferative blockade prevented octreotide inhibition of AP and DP, suggesting that the mitogenic effects of octreotide had simply decreased average maturity of the cells. Octreotide did not alter Caco-2 adhesion, EGF-or matrix-modulated motility, or integrin surface expression. Octreotide appears to directly stimulate Caco-2 proliferation by decreasing cAMP. These proliferative effects modulate Caco-2 differentiation but do not affect cell-matrix interactions.
Sgambati
S A
SA
Department of Surgery, Yale University School of Medicine, University of Connecticut School of Medicine, New Haven 06520-8062, USA.
Zarif
A
A
Basson
M D
MD
D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis / Q000648:ultrastructure; D003994:Bucladesine / Q000494:pharmacology; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D039423:Integrin alpha1; D016023:Integrins / Q000032:analysis / Q000648:ultrastructure; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects*; D007797:Laminin / Q000494:pharmacology; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology; D016685:Mitomycin / Q000494:pharmacology; D015282:Octreotide / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D005765:Gastrointestinal Agents; D039423:Integrin alpha1; D016023:Integrins; D007797:Laminin; D016685:Mitomycin; D004815:Epidermal Growth Factor; D003994:Bucladesine; D003094:Collagen; D000242:Cyclic AMP; D000469:Alkaline Phosphatase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D015282:Octreotide