STAT3 MEDIATES THE SURVIVAL SIGNAL IN ONCOGENIC RAS-TRANSFECTED INTESTINAL EPITHELIAL-CELLS

The oncogenic ras mutation is a common and critical step in gastrointe stinal carcinogenesis. In a previous study, we demonstrated that oncog enic ras activated the EGF-related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras-stimulated cell (I EC-ras cell) was dependent on this activated EGF-related peptide autoc rine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cy tokines, are known to also be activated by EGF. However, the role of S TATs in the survival signal of IEC-ras cells is not clear. In the pres ent study, we demonstrate that STAT3 is constitutively activated in ra s-stimulated cells and that STAT3 activation is considerably suppresse d by the EGF-specific receptor kinase inhibitor AG1478, We also show t hat disruption of the STAT3 pathway by introduction of a dominant-nega tive STAT3 mutant abolishes the apoptosis resistance against UVC and M MC treatment observed in IEC-ras cells without affecting proliferation . Moreover, the expression of Bcl-2 and Bcl-xL, apoptosis-suppressive proteins, is reduced in dominant-negative STAT3-transfected cells. Thu s, STAT3 appears to be an important mediator of the anti-apoptotic sig nal in IEC-ros cells. Int. J, Cancer 78:326-330, 1998, (C) 1998 Wiley- Liss, Inc.