STAT3 mediates the survival signal in oncogenicras-transfected intestinal epithelial cells

Zushi, Shinichiro; Shinomura, Yasuhisa; Kiyohara, Tatsuya; Miyazaki, Yoshiji; Kondo, Shinya; Sugimachi, Masamitsu; Higashimoto, Yoshifumi; Kanayama, Shuji; Matsuzawa, Yūji

doi:10.1002/(sici)1097-0215(19981029)78:3<326::aid-ijc12>3.0.co;2-4

Cited by 116 publications

(70 citation statements)

References 16 publications

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“…Thus, Ag490-induced inhibition of constitutively activated Stat3 is followed by changes in Bcl-2/Bax expression and induction of apoptosis. Considering findings in other cell systems, where Stat3 inhibition was shown to decrease Bcl-2 expression and induce apoptosis, 8,13 we speculate that the Ag490-induced effects are mediated via inhibition of constitutively activated Stat3. However, we can not exclude that other Jak kinase targets might be involved.…”

Section: Inhibition Of Stat3 Activity and Changes In Bcl-2/bax Expresmentioning

confidence: 58%

“…Thus, these observations are in accordance with findings in other cell systems, where inhibition of Stat3 signaling lead to decreased Bcl-2 expression. 8,13 The counter-acting proteins Bcl-2 and Bax, play a key role in regulation of apoptosis. 14 High levels of Bcl-2 have a function in maintaining the normal ion potential across the mitochondrial membrane.…”

Section: Expression Of Bcl-2 and Bax Proteins Is Altered Following Agmentioning

confidence: 99%

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1999

Leukemia

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The Jak/Stat signaling pathway transmits signals from many cytokine and growth factor receptors to target genes in the nucleus. Constitutive activation of Stat3 has recently been observed in many tumor cells and dysregulation of the Stat signaling pathway has been proposed to be implicated in malignant transformation. In a previous study, we found constitutively tyrosine phosphorylated Stat3 in mycosis fungoides tumor cells. Here, we show that the Jak kinase inhibitor, Ag490, inhibits the constitutive binding of Stat3 to an oligonucleotide representing the Stat-binding sequence from the ICAM promotor. The decreased ability of Stat3 to bind DNA precedes dynamic alterations in the expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins (decreased Bcl-2 expression and increased Bax expression) and induction of apoptosis. Thus, our data suggest that the involvement of Stat3 in oncogenic transformation could be mediated through regulation of survival signals.

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Section: Inhibition Of Stat3 Activity and Changes In Bcl-2/bax Expresmentioning

confidence: 58%

Section: Expression Of Bcl-2 and Bax Proteins Is Altered Following Agmentioning

confidence: 99%

True

1999

Leukemia

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“…This indicates that high expression of pStat3 in cancer lesions may be a useful biomarker for poor prognosis in patients with chordoma. Stat3 has been shown to be vital for tumor cell growth, proliferation, and apoptosis (41)(42)(43). Inhibition of Stat3 in model systems has shown a reduction in survival and proliferation of tumor cells (24).…”

Section: Discussionmentioning

confidence: 99%

A novel target for treatment of chordoma: signal transducers and activators of transcription 3

Yang

Schwab

Schoenfeld

et al. 2009

Molecular Cancer Therapeutics

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A major obstacle in the effective treatment of chordoma is that there are no identifiable biomarkers capable of predicting prognosis. Recent research has indicated that signal transducers and activators of transcription (Stat3) may be an important prognostic marker in some cancers, but its role in chordoma tumors has not been elucidated. In this study, the expression of Stat3 was evaluated in chordoma tissue microarray that contains 70 chordoma samples. Cells in the tissue microarray showed nuclear staining for phosphorylated Stat3 in all instances. The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease. Three chordoma cell lines were exposed to SD-1029, a novel inhibitor of Stat3 activation. MTT assay showed that the growth of all chordoma cell lines was inhibited by SD-1029. The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029. In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment.

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“…There is constitutively elevated tyrosine phosphorylation and DNA-binding activity of Stat3 in ®broblasts stably transformed by the Src oncoprotein . Ras-stimulated intestinal cells have constitutively activated Stat3 and this Stat3 activation is suppressed by EGFR-speci®c kinase inhibitors (Zushi et al, 1998). Furthermore, data from transient transfection experiments in HeLa cells, using c-fos promoters lacking the STAT regulatory element c-sis-inducible element, indicate that this element may play a role in the induction of c-fos by EGF in these cells (Leaman et al, 1996).…”

Section: Egfr Signaling and Stat Proteinsmentioning

confidence: 99%