Role of ERK-BIM and STAT3-Survivin Signaling Pathways in ALK Inhibitor-Induced Apoptosis in EML4-ALK-Positive Lung Cancer

• Published in: Clinical cancer research Vol. 17; no. 8; pp. 2140 - 2148
• Main Authors: TAKEZAWA, Ken, OKAMOTO, Isamu, NISHIO, Kazuto, JÄNNE, Pasi A, NAKAGAWA, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-04-2011
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Female; Humans; Immunoblotting; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; NIH 3T3 Cells; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Pneumology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; RNA Interference; Signal Transduction - drug effects; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transfection; Tumors of the respiratory system and mediastinum; Lung disease; Bcl-2 interacting mediator of cell death; Extracellular signal-regulated protein kinase; Enzyme; Respiratory disease; Transferases; Lung cancer; Mitogen-activated protein kinase; Malignant tumor; Survivin; Bronchopulmonary; Signal transduction; Apoptosis inhibitory protein; Signaling pathway; Cell death; C-Onc gene; Transcription factor STAT3; Bronchus disease; Inhibitor; Anaplastic lymphoma kinase; Protooncogene; Cancer; Apoptosis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2798

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.
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.
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.
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.