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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.

Author information

Lee JH1,2, Choi SI1, Kim RK1, Cho EW3, Kim IG4,5.
1
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, Korea.
2
Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-Daero, Yusong-Gu, Daejeon, 305-353, Korea.
3
Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 25 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Korea. ewcho@kribb.re.kr.
4
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, 111, Daedeok-Daero 989 Beon-Gil, Yuseong-Gu, Daejeon, Korea. igkim@kaeri.re.kr.
5
Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), 989-111 Daedeok-Daero, Yusong-Gu, Daejeon, 305-353, Korea. igkim@kaeri.re.kr.