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.
Highlights
Recent studies have shown that cancer stem cells (CSCs) or tumor-initiating cells, a rare undifferentiated fraction of tumor cells with distinct stem cell-like features, are strongly implicated with chemo- or radiation-resistance, metastasis, and high rate of tumor recurrence[1,2]
On the study of the CSC-like characteristics of ALDH1high non-small cell lung cancer (NSCLC) cells, we found that TESC is highly upregulated in ALDH1high CSC-like cells and its overexpression reinforces CSC-like properties of NSCLC cells
We have found that ALDH1high and ALDH1low cells sorted from NSCLC cells have very different gene profiles
Summary
Recent studies have shown that cancer stem cells (CSCs) or tumor-initiating cells, a rare undifferentiated fraction of tumor cells with distinct stem cell-like features, are strongly implicated with chemo- or radiation-resistance, metastasis, and high rate of tumor recurrence[1,2]. ALDH1 is an intracellular detoxifying enzyme that contributes to the oxidation of exogenous and endogenous aldehydes, but it is involved in cell growth and differentiation by oxidation of cellular aldehydes and used as a marker of normal tissue stem cells[8,9]. Identifying the determinants and signaling pathways that regulate ALDH1 expression is important for the establishment of effective strategies targeting CSCs. TESC, which encodes a putative EF-hand Ca2+-binding protein consisting of 214 amino acids, has been first identified in the embryonic testis of mouse and suggested to be involved in gonadal differentiation[14]. Activated IGF1R induced the phosphorylation of STAT, which enhanced ALDH1 expression, followed by reinforcement of the cancer stemness and radioresistance of non-small cell lung cancer (NSCLC) cells. Here we showed TESC as a novel regulator of c-Src/IGF1R-mediated STAT3 activation pathway, which enhances ALDH1 expression, reinforces the CSC-like and radio-resistant properties
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call