EXPRESSION AND TYROSINE PHOSPHORYLATION OF PHOSPHATIDYL-INOSITOL-3 KINASE IN HUMAN GASTRIC-CANCER CELLS - ITS CORRELATION WITH CELL-GROWTH

To reveal the signaling pathway leading to oncogenecity of human cance r cells, we examined the expression and tyrosine-phosphorylation of ph osphatidylinositol (PI)-3 kinase in cancer cell lines. Of the 14 cell lines examined, two poorly differentiated human gastric cancer cell li nes, NUGC-4 and MKN-45, which were previously found to have aberrant e levation of tyrosine phosphorylation showed elevated levels of PI-3 ki nase 85-kDa subunit expression. In these cells, tyrosine-phosphorylati on and overall activity of PI-3 kinase were apparently elevated, compa red with normal human fibroblasts and another well differentiated gast ric cancer cell line, MKN-28. Treatment of these cells with tyrosine k inase inhibitor, genistein, strongly suppressed the PI-3 kinase activi ty. Furthermore, wortmannin, a potent inhibitor of PI-3 kinase, strong ly suppressed the growth of these gastric cancer cells. These results suggest that the growth signaling via tyrosine phosphorylation is requ ired for the activation of PI-3 kinase in NUGC4 and MKN-45, and that t his activation plays an important role in oncogenic growth of these ce lls. However, these two cell lines showed different responses of PI-3 kinase to acid-treatment and tyrosine kinase inhibitors. In MKN-45, ac tivation of PI-3 kinase appeared to be constitutive, and could be rele vant to the oncogenic nature of the cell line.