Selective inhibition of TNF-α-induced activation of mitogen-activated protein kinases and metastatic activities by gefitinib

Ueno, Yoshio; Sakurai, Hiroaki; Matsuo, Mitsuhiro; Choo, Min‐Kyung; Koizumi, Keiichi; Saiki, Ikuo

doi:10.1038/sj.bjc.6602548

Cited by 28 publications

(36 citation statements)

References 32 publications

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“…In HCC cells, ZD1839 (Iressa; Baselga and Averbuch, 2000), which has been primarily applied in lung and breast cancer efficiently reduces tumor cell growth and induces apoptosis (Hopfner et al, 2004) and appears to inhibit metastatic activity of HCC cells (Ueno et al, 2005). Also, OSI-774 (erlotinib;Pollack et al, 1999) inhibits tumor cell growth of HCC cells based on elevated apoptosis (Huether et al, 2005b).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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Section: Therapeutic Approachesmentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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“…The second paper showed that TNF activates MAPKs when EGFR is blocked in HeLa cells (28). Other studies, however, indicate ERK/MAPK as a target of TNF-transactivated EGFR (13,29). We have reported previously that TNF initiates antiapoptotic signaling pathways through kinase suppressor of Ras (KSR) in intestinal epithelial cells (4,5) with KSR required for TNF activation of ERK1/2 MAPK and IB degradation in YAMC cells (4,5).…”

Section: Fig 4 Suppression Of Egfr and Erbb2 Expression Promotes Apmentioning

confidence: 99%

Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis

Yamaoka¹,

Yan²,

Cao³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

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TNF is a pleiotropic cytokine that activates both anti-and proapoptotic signaling pathways, with cell fate determined by the balance between these two pathways. Activation of ErbB family members, including EGF receptor (EGFR/ErbB1), promotes cell survival and regulates several signals that overlap with those stimulated by TNF. This study was undertaken to determine the effects of TNF on EGFR and ErbB2 activation and intestinal epithelial cell survival. Mice, young adult mouse colon epithelial cells, and EGFR knockout mouse colon epithelial cells were treated with TNF. Activation of EGFR, ErbB2, Akt, Src, and apoptosis were determined in vivo and in vitro. TNF stimulated EGFR phosphorylation in young adult mouse colon epithelial cells, and loss of EGFR expression or inhibition of kinase activity increased TNF-induced apoptosis, which was prevented in WT but not by kinase-inactive EGFR expression. Similarly, TNF injection stimulated apoptosis in EGFR-kinasedefective mice (EGFR wa2 ) compared with WT mice. TNF also activated ErbB2, and loss of ErbB2 expression increased TNF-induced apoptosis. Furthermore, Src-kinase activity and the expression of both EGFR and ErbB2 were required for TNF-induced cell survival. Akt was shown to be a downstream target of TNF-activated EGFR and ErbB2. These findings demonstrate that EGFR and ErbB2 are critical mediators of TNF-regulated antiapoptotic signals in intestinal epithelial cells. Given evidence for TNF signaling in the development of colitis-associated carcinoma, this observation has significant implications for understanding the role of EGFR in maintaining intestinal epithelial cell homeostasis during cytokinemediated inflammatory responses.

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“…17 The sequences of the primers were as follows: MMP-9, Real-time RT-PCR was performed as previously described. 17 The sequences of the primers were as follows: VEGFA 5 0 -GTGCACTGGACCCT-3 0 and 5 0 -GGTCTCAATCGGACGG-3 0 , GAPDH 5 0 -AAATGGT-GAAGGTCGGTGTG-3 0 and 5 0 -TGAAGGGGTCGTTGATGG-3 0 .…”

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Ueno

Sakurai

Tsunoda

et al. 2008

Intl Journal of Cancer

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ErbB3 receptor tyrosine kinase has been shown to induce tumor progression in several types of cancer through heterodimerization with ErbB2. However, the role of ErbB3 and its ligand heregulin (HRG) in tumor metastasis remains poorly understood. In the present study, we tried to clarify their contributions to the metastasis of ErbB3-overexpressing B16-BL6 melanoma cells. Stimulation with HRG induced phosphorylation of ErbB3 and metastatic properties including MMP-9 expression, invasion, adhesion and experimental lung metastasis in vivo. These cellular responses were blocked by inhibiting the tyrosine kinase activity of EGFR with PD153035. In addition, phosphorylation of EGFR was rapidly induced by HRG, suggesting that EGFR is a possible heterodimeric counterpart of ErbB3. RNA interference demonstrated that subcutaneous tumor growth and angiogenesis was attenuated by inactivation of ErbB3 in cancer cells. Although experimental pulmonary metastasis was not affected by the knockdown of ErbB3, spontaneous metastasis was, even when primary tumors in the foot pad were amputated at a similar size. These results indicate that HRG-induced activation of ErbB3 via EGFR promotes tumor growth and metastasis of melanoma cells. ' 2008 Wiley-Liss, Inc.Key words: ErbB3; EGFR; heregulin; metastasis; melanoma The receptor tyrosine kinase (RTK) family of ErbBs forms part of a complex signal cascade modulating cell proliferation, survival and adhesion. The family comprises 4 homologous receptors, EGFR, ErbB2, ErbB3 and ErbB4, which form homodimers or heterodimers to initiate intracellular signaling in response to their ligands. EGFR and ErbB2 have recently been focused on the molecular targeted therapy of cancer, because overexpression, amplification and mutations are involved in carcinogenesis and the progression of several types of cancer including metastasis. 1-3Tyrosine kinase inhibitors and neutralizing monoclonal antibodies against these receptors are clinically approved for the treatment of nonsmall cell lung cancer (NSCLC) and breast cancer. In addition to tumorigenesis, these receptors have also been shown to contribute to metastasis. 4,5 In spite of no high affinity ligand for ErbB2 and the inactive kinase domain of ErbB3, the ErbB2/ErbB3 heterodimer is believed to be the most biologically active and tumorigenic of the possible heterodimer complexes of ErbB3.6-8 It has been reported that 20-30% of human breast cancers overexpress ErbB2.9 ErbB3 expression is also reported to be closely associated with relapse-free and overall survival and is associated with a high risk of metastasis among patients with NSCLC.10 In breast cancer ErbB3-dependent signaling through the ErbB3/ErbB2 heterodimer contributes to metastasis by enhancing tumor cell invasion and intravasation. 11In comparison to the ErbB2/ErbB3 heterodimer, little is known about the tumorigenic and metastatic functions of the EGFR/ ErbB3 heterodimer. In addition, while the ErbB3 in other cancers is being studied, the role of ErbB3 in the metastasis of melanoma cells re...

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Selective inhibition of TNF-α-induced activation of mitogen-activated protein kinases and metastatic activities by gefitinib

Cited by 28 publications

References 32 publications

Dysregulation of growth factor signaling in human hepatocellular carcinoma

Dysregulation of growth factor signaling in human hepatocellular carcinoma

Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

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