Calcium channel α2δ1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines

• Published in: Cancer management and research Vol. 10; pp. 5009 - 5018
• Main Authors: Sui, Xin, Geng, Jian-Hao, Li, Yong-Heng, Zhu, Guang-Ying, Wang, Wei-Hu
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 2018; Dove Medical Press
• Subjects: Apoptosis; Ataxia; Breast cancer; calcium channel; cancer stem cell; Cancer therapies; Cell cycle; Chemotherapy; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA damage; DNA damage repair; Efficiency; Gene expression; Immunoglobulins; Kinases; Leukemia; Lung cancer; Original Research; Potassium; Radiation therapy; radioresistance; Respiratory diseases; Stem cells; Thoracic surgery; Tumors; Beijing China; United Kingdom > UK; United States > US; China; calcium channel; DNA damage repair; cancer stem cell; radioresistance
• ISSN: 1179-1322; 1179-1322
• DOI: 10.2147/CMAR.S176084

Radiotherapy is a major treatment method for patients with non-small cell lung cancer (NSCLC). However, the presence of radioresistant cancer stem cells (CSCs) may be associated with disease relapse or a poor outcome after radiotherapy. Voltage-gated calcium channel α2δ1 subunit (encoded by the gene ) isoform 5 is a marker of CSCs in hepatocellular carcinoma. This study aimed to investigate the radiosensitivity of α2δ1-high cells in NSCLC cell lines. NSCLC cell lines A549, H1975, H1299, and PC9 were used. -knockdown and -overexpressing cell lines were established by lentiviral infection. Colony formation assay was performed to determine radiosensitivity. Sphere formation assay in serum-free medium was performed to evaluate self-renewal capacity. Proteins associated with DNA damage repair were analyzed by immunofluorescence or Western blot. The monoclonal antibody of α2δ1 was applied alone or in combination with radiation either in vitro or in vivo to determine the anti-tumor effect of the antibody. α2δ1-high cells showed greater sphere-forming efficiency than α2δ1-low cells and were relatively resistant to radiation. knockdown in A549 cells enhanced radiosensitivity, whereas overexpression in PC9 and H1975 cells reduced radiosensitivity, suggesting that α2δ1 imparted radioresistance to NSCLC cells. Analysis of proteins involved in DNA damage repair suggested that α2δ1 enhanced the efficiency of DNA damage repair. The monoclonal antibody of α2δ1 had a synergistic effect with that of radiation to block the self-renewal of α2δ1-high cells and enhanced the radiosensitivity of α2δ1-positive cells in colony formation assays. The combination of the α2δ1 antibody with radiation repressed A549 xenograft growth in vivo. α2δ1 enhances radioresistance in cancer stem-like cells in NSCLC. The α2δ1 monoclonal antibody sensitizes α2δ1-high cells to radiation, suggesting that the antibody may be used to improve the treatment outcome when combined with radiation in NSCLC.