Abstract
Studies have shown that cancer stem cells (CSCs) are involved in resistance and metastasis of cancer; thus, therapies targeting CSCs have been proposed. Here, we report that heat shock 70-kDa protein 1-like (HSPA1L) is partly involved in enhancing epithelial–mesenchymal transition (EMT) and CSC-like properties in non-small cell lung cancer (NSCLC) cells. Aldehyde dehydrogenase 1 (ALDH1) is considered a CSC marker in some lung cancers. Here, we analyzed transcriptional changes in genes between ALDH1high and ALDH1low cells sorted from A549 NSCLC cells and found that HSPA1L was highly expressed in ALDH1high cells. HSPA1L played two important roles in enhancing CSC-like properties. First, HSPA1L interacts directly with IGF1Rβ and integrin αV to form a triple complex that is involved in IGF1Rβ activation. HSPA1L/integrin αV complex-associated IGF1Rβ activation intensified the EMT-associated cancer stemness and γ-radiation resistance through its downstream AKT/NF-κB or AKT/GSK3β/β-catenin activation pathway. Secondly, HSPA1L was also present in the nucleus and could bind directly to the promoter region of β-catenin to function as a transcription activator of β-catenin, an important signaling protein characterizing CSCs by regulating ALDH1 expression. HSPA1L may be a novel potential target for cancer treatment because it both enhances IGF1Rβ activation and regulates γβ-catenin transcription, accumulating CSC-like properties.
Highlights
Cancer stem cells (CSCs), first revealed in acute myeloid leukemia, exist in a variety of solid tumors, including lung cancer [1,2,3]
HSPA1L Was Upregulated in ALDH1high Cells Isolated from A549 Cells
Despite accumulating evidence that Aldehyde dehydrogenase 1 (ALDH1) plays an important role in CSC properties, studies related to specific mechanisms and pathways involved in regulating ALDH1 expression are still insufficient
Summary
Cancer stem cells (CSCs), first revealed in acute myeloid leukemia, exist in a variety of solid tumors, including lung cancer [1,2,3]. Non-small cell lung cancer (NSCLC) is difficult to treat because it is resistant to anticancer agents, such as ionizing radiation and chemical-targeted drugs. Aldehyde dehydrogenase 1 (ALDH1), which is involved in self-renewal, differentiation and detoxification, is overexpressed in cells from lung cancer patients with poor prognoses [14,15]. We showed that upregulated HSPA1L in ALDH1high cells sorted from NSCLC A549 cells was involved in insulin-like growth factor-1 receptor β IGF1Rβ activation and enhanced the CSC-like properties, resistance, and malignancy via either the AKT/NF-κB or AKT/GSK3β/β-catenin signaling pathways. HSPA1L was directly involved in the transcription of β-catenin, a transcription regulator of ALDH1 expression
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