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Endocrinology Vol. 140, No. 2 765-777
Copyright © 1999 by The Endocrine Society

ARTICLES

Inhibitory and Stimulatory Effects of Somatostatin on Two Human Pancreatic Cancer Cell Lines: A Primary Role for Tyrosine Phosphatase SHP-11

Nadine Douziech, Ezéquiel Calvo, Zoé Coulombe2, Gauri Muradia, Jacinthe Bastien, Rémy A. Aubin, Ana Lajas3 and Jean Morisset

Service de gastroentérologie (N.D., E.C., Z.C., J.M.), Départment Médecine, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4; Health Canada (G.M., R.A.A.), Therapeutic Drugs Programme, Life Sciences Division, Biotechnology Section, PLC2201C, Sir F. G. Banting Research Centre, Tunney’s Pasture, Ottawa, Ontario, Canada, K1A 0L2; Department of Biochem. Immunol. Microbiol.(J.B., R.A.A.), Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5; and Department Physiology (A.L.), Faculty of Veterinary Sciences, University of Extremadura, 10.07 Caceres, Spain

Address all correspondence and requests for reprints to: Dr. Jean Morisset, Service de Gastroentérologie, Département Médecine, Faculté Médecine, Sherbrooke, Québec, Canada, J1H5N4. E-mail: jmori7{at}courrier.usherb.ca

Somatostatin (SS-14) and its structural analogue SMS 201–995 (SMS) are recognized as physiological inhibitors of multiple organs and tissue functions through specific membrane receptors (sst1–sst5). The effects of SS-14 and SMS in the growth control of the pancreatic cancer cell lines MIA PaCa-2 and PANC-1 were investigated to identify and clarify the intracellular events involved. In PANC-1 cells, SS-14 and SMS caused inhibition of their basal growth, and that stimulated by epidermal growth factor, with a maximal effect at 0.1–1 µM. To understand the inhibitory mechanisms, we investigated the effects of SS-14 and SMS on phosphotyrosine phosphatase (PTPase) activity and, more specifically, that of tyrosine phosphatase SHP-1 (PTP1C). SS-14 and SMS caused significant increases in total cellular PTPase activity, and particularly SHP-1, with maximal activation within 1 min. Inhibition of membrane tyrosine kinase and p42 MAP kinase activities was also observed, in response to SS-14 and SMS. In MIA PaCa-2 cells, SS-14 and SMS were associated with a positive growth response at 1–10 nM, after 4 days of culture in serum-free medium. Total cellular PTPase activity was slightly increased, but SHP-1 activity could not be detected; its absence in this cell line was confirmed by Western blot. Membrane tyrosine kinase activities were significantly increased by SS-14 and SMS at concentrations needed for maximal growth. p44/p42, which are constitutively active in this cell line, and p38 activities were not affected by somatostatin. In conclusion, somatostatin can exert different effects on human pancreatic cancer cell growth, depending upon the presence or absence of SHP-1. This enzyme can play a key role in the control of cell proliferation, and its cellular presence may determine the therapeutic potential of somatostatin in the control of cancer cell growth.




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