INDUCTION OF A NEGATIVE AUTOCRINE LOOP BY EXPRESSION OF SST2 SOMATOSTATIN RECEPTOR IN NIH 3T3 CELLS

The somatostatin receptor subtype sst2 mediates both activation of a t yrosine phosphatase activity and inhibition of cell proliferation indu ced by somatostatin analogues, In the absence of exogenous ligand, exp ression of sst2 in NIH 3T3 cells resulted in inhibition of cell growth . Polymerase chain reaction coupled to reverse transcription demonstra ted that expression of sst2 in NIH 3T3 cells stimulated the expression of preprosomatostatin mRNA accompanied by a production of immunoreact ive somatostatin-like peptide which corresponded predominantly to soma tostatin 14. Moreover anti-somatostatin antibodies suppressed sst2-pro moted inhibition of cell proliferation. Inhibition of cell proliferati on associated with increased secretion of somatostatin-like immunoreac tivity was also observed after expression of sst2 in human pancreatic tumor cells BxPC3 devoid of endogenous receptors. In addition, express ion of sst2 in NIH 3T3 cells was associated with the constitutive acti vation of tyrosine phosphatase PTP1C that resulted from enhanced expre ssion of the protein. Blocking of PTP1C tyrosine phosphatase activity with orthovanadate or that of PTP1C protein with antisense PTP1C oligo nucleotides decreased the sst2-induced inhibition of cell proliferatio n. These results, taken together, show that expression of sst2 in NIH 3T3 cells generated a negative autocrine loop by stimulating sst2 liga nd production and amplifying PTP1C sst2-transducer. Sst2/ligand may fu nction as a determinant factor involved in the negative growth control of cells.