Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells

生物 癌症研究 原癌基因酪氨酸蛋白激酶Src 酪氨酸激酶 车站3 受体酪氨酸激酶 信号转导 JAK-STAT信号通路 贾纳斯激酶 STAT蛋白 酪氨酸磷酸化 激酶 细胞生物学 分子生物学
作者
Roy Garcia,Tammy Bowman,Guilian Niu,Hua Yu,Sue Minton,Carlos Muro‐Cacho,Charles E. Cox,Robert E. Falcone,Rita Fairclough,Sarah J. Parsons,Andy Laudano,Aviv Gazit,Alexander Levitzki,Alan J. Kraker,Richard Jove
出处
期刊:Oncogene [Springer Nature]
卷期号:20 (20): 2499-2513 被引量:742
标识
DOI:10.1038/sj.onc.1204349
摘要

Constitutive activation of signal transducer and activator of transcription (STAT) proteins has been detected in a wide variety of human primary tumor specimens and tumor cell lines including blood malignancies, head and neck cancer, and breast cancer. We have previously demonstrated a high frequency of Stat3 DNA-binding activity that is constitutively-induced by an unknown mechanism in human breast cancer cell lines possessing elevated EGF receptor (EGF-R) and c-Src kinase activities. Using tyrosine kinase selective inhibitors, we show here that Src and JAK family tyrosine kinases cooperate to mediate constitutive Stat3 activation in the absence of EGF stimulation in model human breast cancer cell lines. Inhibition of Src or JAKs results in dose-dependent suppression of Stat3 DNA-binding activity, which is accompanied by growth inhibition and induction of programmed cell death. In addition, transfection of a dominant-negative form of Stat3 leads to growth inhibition involving apoptosis of breast cancer cells. These results indicate that the biological effects of the Src and JAK tyrosine kinase inhibitors are at least partially mediated by blocking Stat3 signaling. While EGF-R kinase activity is not required for constitutive Stat3 activation in breast cancer cells, EGF stimulation further increases STAT DNA-binding activity, consistent with an important role for EGF-R in STAT signaling and malignant progression. Analysis of primary breast tumor specimens from patients with advanced disease revealed that the majority exhibit elevated STAT DNA-binding activity compared to adjacent non-tumor tissues. Our findings, taken together, suggest that tyrosine kinases transduce signals through Stat3 protein that contribute to the growth and survival of human breast cancer cells in culture and potentially in vivo.

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