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Glutamine Modulates Phenotype and Stimulates Proliferation in Human Colon Cancer Cell Lines¹

Departments of Surgery [G. A. T., Z. R., F. H., M. D. B.] and Pathology [J. A. M.], Yale University School of Medicine, New Haven, Connecticut 06510, and the West Haven VA Hospital [Z. R., F. H., M. D. B.], West Haven, Connecticut 06516

Glutamine supplementation has been advocated for patients requiring parenteral nutritional support. However, the direct effect of glutamine on neoplastic cells is poorly understood. We therefore investigated the effects of glutamine on the proliferation, differentiation, and cell-matrix interactions of two human colon carcinoma cell lines (Caco-2 and SW620) adapted to glutamine-free media. Doubling times were calculated by logarithmic transformation of serial cell counts. Alkaline phosphatase, cathepsin C (dipeptidyl peptidase), lactase, and isomaltase expression (markers of differentiation) were assayed by digestion of synthetic substrates. Adhesion to matrix proteins was assessed by colorimetric quantitation of toluidine blue staining of adherent cells. Surface expression of Caco-2 receptors for matrix proteins (integrins) was studied by biotinylation and immunoprecipitation with specific antibodies. Glutamine (1–10 mM) dose-dependently stimulated Caco-2 proliferation on all matrices studied with maximal effect at 7 mM. For instance, Caco-2 doubling time on collagen IV decreased by 57 ± 0.2% (SE) (P < 0.001). Glutamine inhibited the expression of all four digestive enzymes with maximal inhibition ranging from 10 to 40% (P < 0.05 for all). Adhesion to matrix proteins was markedly diminished (51 ± 1%, P < 0.01) by glutamine (5 mM) treatment, correlating with decreased 2 and ß1 integrin subunit surface expression. Glutamine had similar effects on SW620 cells, stimulating proliferation, inhibiting digestive enzyme expression, and diminishing both adhesion and integrin surface expression. Glutamine supplementation modulates the phenotype of at least two human colon carcinoma cell lines, increasing proliferation, decreasing differentiation, and decreasing adhesion to matrix proteins in association with decreased integrin expression. Although the mechanisms of these effects await elucidation, such characteristics would appear to predict more aggressive tumor behavior and raise the possibility that nutritional supplementation with glutamine may be deleterious in patients with cancer.

¹ Funded by Donaghue Foundation New Investigator Award 041 and a Hull Cancer Research Award (M. D. B.), NIH Grant ROIHL 28373 (J. A. M.), with additional support from St. Mary's Hospital (G. A. T.) and the Bridgeport Hospital Medical Research Fund (Z. R.).

² To whom requests for reprints should be addressed, at Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Received 3/16/94. Accepted 9/27/94.

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