Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

Scientific Reports
Jei Ha LeeIn-Gyu Kim

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 ass...Continue Reading

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Citations

May 1, 2019·Journal of Experimental & Clinical Cancer Research : CR·Wen-Chien HuangYongjie Wang
Sep 13, 2019·Journal of Experimental & Clinical Cancer Research : CR·So-Yeon ParkJeong-Seok Nam
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Aug 1, 2020·Frontiers in Oncology·Xuehai WangNing Yang
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Pei-Chin ChenYen-Hua Huang
Mar 7, 2021·Biomolecules·Caterina MancarellaKatia Scotlandi
Jun 24, 2021·Molecular Cancer Therapeutics·Hong Shik YunKevin Camphausen

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Methods Mentioned

BETA
flow cytometry
xenograft
transfection
immunoprecipitation
Fluorescence-activated cell sorting
FACS
ChIP
nuclear translocation
xenografts
PCR

Software Mentioned

PRISM
GraphPad

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