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STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells
S Zushi1, Y Shinomura, T Kiyohara
1Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan. fwgj9902@mb.infoweb.or.jp
Abstract:
The oncogenic ras mutation is a common and critical step in gastrointestinal carcinogenesis. In a previous study, we demonstrated that oncogenic ras activated the EGF-related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras-stimulated cell (IEC-ras cell) was dependent on this activated EGF-related peptide autocrine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cytokines, are known to also be activated by EGF. However, the role of STATs in the survival signal of IEC-ras cells is not clear. In the present study, we demonstrate that STAT3 is constitutively activated in ras-stimulated cells and that STAT3 activation is considerably suppressed by the EGF-specific receptor kinase inhibitor AG 1478. We also show that disruption of the STAT3 pathway by introduction of a dominant-negative STAT3 mutant abolishes the apoptosis resistance against UVC and MMC 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. Thus, STAT3 appears to be an important mediator of the antiapoptotic signal in IEC-ras cells.
Insights
Oncogenic ras mutations activate signal transducers and activators of transcription 3 (STAT3), promoting cancer cell survival. STAT3 mediates resistance to apoptosis in gastrointestinal cancer cells by upregulating anti-apoptotic proteins.
Area of Science:
- Gastrointestinal carcinogenesis
- Cellular signaling pathways
- Oncology
Background:
- Oncogenic ras mutations are key in gastrointestinal cancer development.
- Ras activation triggers an EGF-related peptide autocrine loop, conferring apoptosis resistance.
- The role of signal transducers and activators of transcription (STATs) in ras-induced cell survival was unclear.
Purpose of the Study:
- To investigate the role of STATs, specifically STAT3, in the survival signaling of ras-stimulated gastrointestinal cancer cells.
- To determine if STAT3 activation is essential for the apoptosis resistance observed in these cells.
Main Methods:
- Constitutive activation of STAT3 in ras-stimulated cells (IEC-ras) was assessed.
- The effect of an EGF receptor kinase inhibitor (AG 1478) on STAT3 activation was evaluated.
- Apoptosis resistance was examined in IEC-ras cells with disrupted STAT3 signaling using a dominant-negative STAT3 mutant.
- The expression of apoptosis-suppressive proteins Bcl-2 and Bcl-xL was analyzed.
Main Results:
- STAT3 was found to be constitutively activated in ras-stimulated cells.
- STAT3 activation was significantly inhibited by AG 1478.
- Disruption of STAT3 signaling abolished apoptosis resistance to UVC and MMC treatments without affecting cell proliferation.
- Expression of Bcl-2 and Bcl-xL was reduced in cells expressing dominant-negative STAT3.
Conclusions:
- STAT3 is constitutively activated in ras-stimulated gastrointestinal cancer cells.
- STAT3 acts as a crucial mediator of the anti-apoptotic signal in these cells.
- Targeting the STAT3 pathway may offer a therapeutic strategy for gastrointestinal cancers with ras mutations.