| Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. | |
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MedLine Citation:
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PMID: 21415216 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: EML4-ALK was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK.EXPERIMENTAL DESIGN: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK.RESULTS: Forced expression of EML4-ALK induced marked activation of ERK and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by up-regulation of BIM, a proapoptotic member of the Bcl-2 family, and by down-regulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively.CONCLUSIONS: ALK inhibitor-induced apoptosis is mediated both by BIM up-regulation resulting from inhibition of ERK signaling as well as by survivin down-regulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. |
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Authors:
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Ken Takezawa; Isamu Okamoto; Kazuto Nishio; Pasi Janne; Kazuhiko Nakagawa |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-17 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: - ISSN: 1078-0432 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Medical Oncology, Kinki University School of Medicine. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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