HSPA1L Enhances Cancer Stem Cell-Like Properties by Activating IGF1Rβ and Regulating β-Catenin Transcription

• Published in: International journal of molecular sciences Vol. 21; no. 18; p. 6957
• Main Authors: Choi, Soo-Im, Lee, Jei-Ha, Kim, Rae-Kwon, Jung, Uhee, Kahm, Yeon-Jee, Cho, Eun-Wie, Kim, In-Gyu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 22.09.2020; MDPI AG
• Subjects: A549 Cells; ALDH1; beta Catenin - biosynthesis; beta Catenin - genetics; cancer stem cell; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; EMT; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; HSPA1L; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Transcription, Genetic; β-catenin; β-catenin; HSPA1L; cancer stem cell; ALDH1; EMT
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21186957

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.