Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M, Higashimoto Y, Kanayama S, Matsuzawa Y
Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan.
Int J Cancer. 1998 Oct 29;78(3):326-30. doi: 10.1002/(SICI)1097-0215(19981029)78:3<326::AID-IJC12>3.0.CO;2-4.
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.
致癌性Ras突变是胃肠癌发生过程中常见且关键的一步。在之前的一项研究中，我们证明致癌性Ras激活了表皮生长因子（EGF）相关肽自分泌环，并且在致癌性Ras刺激的细胞（IEC-ras细胞）中观察到的抗凋亡作用依赖于这种激活的EGF相关肽自分泌环。信号转导子和转录激活子（STATs）最初被鉴定为受细胞因子刺激的细胞内信号转导子，已知其也可被EGF激活。然而，STATs在IEC-ras细胞存活信号中的作用尚不清楚。在本研究中，我们证明STAT3在Ras刺激的细胞中持续激活，并且STAT3的激活被EGF特异性受体激酶抑制剂AG 1478显著抑制。我们还表明，通过引入显性负性STAT3突变体破坏STAT3途径，可消除IEC-ras细胞中观察到的对紫外线C（UVC）和丝裂霉素C（MMC）处理的抗凋亡作用，而不影响细胞增殖。此外，在转染显性负性STAT3的细胞中，抗凋亡蛋白Bcl-2和Bcl-xL的表达降低。因此，STAT3似乎是IEC-ras细胞中抗凋亡信号的重要介质。
