OCTREOTIDE DIFFERENTIALLY MODULATES HUMAN CACO-2 INTESTINAL EPITHELIAL-CELL PROLIFERATION AND DIFFERENTIATION BY DECREASING INTRACELLULAR CAMP

Somatostatin modulates gastrointestinal mucosal growth and differentia tion indirectly via inhibition of bioactive peptides and directly by l ess well understood mechanisms. We studied the direct effects of the s omatostatin analog octreotide on proliferation, brush-border enzyme ac tivity, cell-matrix interactions and intracellular cAMP in Caco-2 huma n intestinal epithelial cells. Proliferation was assessed by cell coun ting and [H-3]thymidine uptake. The brush-border enzymes alkaline phos phatase (AP) and dipeptidyl dipeptidase (DP) were quantitated by synth etic substrate digestion. Adhesion and migration on purified matrix pr oteins were also measured. Octreotide (10(-9)-10(-5) M) shortened doub ling time (46.5 +/- 6.2% at 10(-5) M, n = 20, P < 0.0001) and stimulat ed [H-3]thymidine uptake. Octreotide decreased intracellular cAMP by 1 9.4 +/- 5.0% (n = 7, P < 0.0001) while dibutyryl-cAMP (10(-6) M) prolo nged doubling time by 10.1 +/- 1.5% (n = 8, P < 0.0001), and blocked t he octreotide effect. Octreotide decreased AP and DP with maximal effe ct at 10(-6) M (36.8 +/- 8.3% and 20.5 +/- 9.1%, n > 7, P < 0.0005 res pectively). However, mitomycin proliferative blockade prevented octreo tide inhibition of AP and DP, suggesting that the mitogenic effects of octreotide had simply decreased average maturity of the cells. Octreo tide did not alter Caco-2 adhesion, EGF-or matrix-modulated motility, or integrin surface expression. Octreotide appears to directly stimula te Caco-2 proliferation by decreasing cAMP. These proliferative effect s modulate Caco-2 differentiation but do not affect cell-matrix intera ctions.