Inhibitory and stimulatory effects of somatostatin on two human pancreaticcancer cell lines: A primary role for tyrosine phosphatase SHP-1

Somatostatin (SS-14) and its structural analogue SMS 201-995 (SMS) are reco gnized as physiological inhibitors of multiple organs and tissue functions through specific membrane receptors (sst1-sst5). The effects of SS-14 and S MS 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 g rowth, and that stimulated by epidermal growth factor, with a maximal effec t at 0.1-1 mu M. To understand the inhibitory mechanisms, we investigated t he effects of SS-14 and SMS on phosphotyrosine phosphatase (PTPase) activit y and, more specifically, that of tyrosine phosphatase SHP-1 (PTP1C). SS-14 and SMS caused significant increases in total cellular PTPase activity, an d particularly SHP-1, with maximal activation within 1 min. Inhibition of m embrane 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 associa ted with a positive growth response at 1-10 mu M, after 4 days of culture i n serum-free medium. Total cellular PTPase activity was slightly increased, but SHP-1 activity could not be detected; its absence in this cell line wa s confirmed by Western blot. Membrane tyrosine kinase activities were signi ficantly increased by SS-14 and SMS at concentrations needed for maximal gr owth. p44/p42, which are constitutively active in this cell line, and p38 a ctivities were not affected by somatostatin. In conclusion, somatostatin ca n 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 gro wth.