Abstract
Tescalcin (TESC; also known as calcineurin B homologous protein 3, CHP3) has recently reported as a regulator of cancer progression. Here, we showed that the elevation of TESC in non-small cell lung cancer (NSCLC) intensifies epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, consequently enhancing the cellular resistance to γ-radiation. TESC expression and the phosphorylation (consequent activation) of signal transducer and activator of transcription 3 (STAT3) were upregulated in CSC-like ALDH1high cells than in ALDH1low cells sorted from A549 NSCLC cells. Knockdown of TESC suppressed CSC-like properties as well as STAT3 activation through inhibition of insulin-like growth factor 1 receptor (IGF1R), a major signaling pathway of lung cancer stem cells. TESC activated IGF1R by the direct recruitment of proto-oncogene tyrosine kinase c-Src (c-Src) to IGF1Rβ complex. Treatment of IGF1R inhibitor, AG1024, also suppressed c-Src activation, implicating that TESC mediates the mutual activation of c-Src and IGF1R. STAT3 activation by TESC/c-Src/IGF1R signaling pathway subsequently upregulated ALDH1 expression, which enhanced EMT-associated CSC-like properties. Chromatin immunoprecipitation and luciferase assay demonstrated that STAT3 is a potential transcription activator of ALDH1 isozymes. Ultimately, targeting TESC can be a potential strategy to overcome therapeutic resistance in NSCLC caused by augmented EMT and self-renewal capacity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Aldehyde Dehydrogenase / metabolism*
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Aldehyde Dehydrogenase 1 Family
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Animals
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CSK Tyrosine-Protein Kinase
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology*
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Carcinoma, Non-Small-Cell Lung / radiotherapy
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / radiation effects
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Female
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Gene Knockdown Techniques
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Humans
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Lung Neoplasms / pathology*
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Lung Neoplasms / radiotherapy
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Mice
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / pathology*
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Neoplastic Stem Cells / radiation effects
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Proto-Oncogene Mas
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RNA, Small Interfering / metabolism
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Radiation Tolerance / drug effects
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Radiation-Sensitizing Agents / administration & dosage
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Receptor, IGF Type 1
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Receptors, Somatomedin / antagonists & inhibitors
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Receptors, Somatomedin / metabolism
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Retinal Dehydrogenase
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STAT3 Transcription Factor / metabolism*
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Tyrphostins / administration & dosage
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Xenograft Model Antitumor Assays
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src-Family Kinases / metabolism
Substances
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Calcium-Binding Proteins
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IGF1R protein, human
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MAS1 protein, human
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Proto-Oncogene Mas
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RNA, Small Interfering
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Radiation-Sensitizing Agents
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Receptors, Somatomedin
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STAT3 Transcription Factor
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STAT3 protein, human
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TESC protein, human
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Tyrphostins
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tyrphostin AG 1024
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Aldehyde Dehydrogenase 1 Family
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Aldehyde Dehydrogenase
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ALDH1A1 protein, human
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Retinal Dehydrogenase
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Receptor, IGF Type 1
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human