Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel α2δ1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer

• Published in: Clinical cancer research Vol. 24; no. 9; pp. 2148 - 2158
• Main Authors: Yu, Jiangyong, Wang, Shuhang, Zhao, Wei, Duan, Jianchun, Wang, Zhijie, Chen, Hanxiao, Tian, Yanhua, Wang, Di, Zhao, Jun, An, Tongtong, Bai, Hua, Wu, Meina, Wang, Jie
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2018
• Subjects: Biotechnology; Calcium; Calcium channels (voltage-gated); Cancer; Cell culture; Cell self-renewal; Chemoresistance; Chemotherapy; Drug resistance; Electric potential; Experimental design; Gene expression; Lung cancer; Monoclonal antibodies; Properties (attributes); Small cell lung carcinoma; Stem cells; Western blotting; Xenografts; Xenotransplantation
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1932

Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α2δ1-mediated chemoresistance and strategies of overcoming the resistance. Experimental Design: α2δ1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in α2δ1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α2δ1-mediated chemoresistance were examined. Results: Different proportions of α2δ1+ cells were identified in SCLC cell lines and PDX models. α2δ1+ cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of α2δ1+ cells instead of CD133+ cells in PDXs, and an increased proportion of α2δ1+ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α2δ1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models. Conclusions: SCLC cells expressing α2δ1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α2δ1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148–58. ©2018 AACR.