Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer

Ken Takezawa, Isamu Okamoto, Kazuto Nishio, Pasi A. Jänne, Kazuhiko Nakagawa

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)

Abstract

Purpose: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) 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 extracellular signal-regulated kinase (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 upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation 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 upregulation of BIM and downregulation 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 upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells.

Original languageEnglish
Pages (from-to)2140-2148
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Apr 15 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer'. Together they form a unique fingerprint.

Cite this