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

Q1 · MEDICINE

Article

Author: Tian, Yanhua ; Chen, Hanxiao ; Wu, Meina ; Wang, Zhijie ; Zhao, Jun ; Zhao, Wei ; Wang, Shuhang ; Bai, Hua ; Duan, Jianchun ; Yu, Jiangyong ; Wang, Jie ; An, Tongtong ; Wang, Di

AbstractPurpose: 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.

01 Apr 2013·Cancer CellQ1 · MEDICINE

1B50-1, a mAb Raised against Recurrent Tumor Cells, Targets Liver Tumor-Initiating Cells by Binding to the Calcium Channel α2δ1 Subunit

Q1 · MEDICINE

Article

Author: Yu Wang ; Wei Zhao ; Kemin Jin ; Zhiqian Zhang ; Baocai Xing ; Fengmin Lu ; Haibo Han ; Weigang Fang ; Limin Wang ; Heping Cheng ; Yangde Chen ; Na Lin ; Ting Guo

The identification and targeted therapy of cells involved in hepatocellular carcinoma (HCC) recurrence remain challenging. Here, we generated a monoclonal antibody against recurrent HCC, 1B50-1, that bound the isoform 5 of the α2δ1 subunit of voltage-gated calcium channels and identified a subset of tumor-initiating cells (TICs) with stem cell-like properties. A surgical margin with cells detected by 1B50-1 predicted rapid recurrence. Furthermore, 1B50-1 had a therapeutic effect on HCC engraftments by eliminating TICs. Finally, α2δ1 knockdown reduced self-renewal and tumor formation capacities and induced apoptosis of TICs, whereas its overexpression led to enhanced sphere formation, which is regulated by calcium influx. Thus, α2δ1 is a functional liver TIC marker, and its inhibitors may serve as potential anti-HCC drugs.

100 Deals associated with 1B50-1 (Peking University Health Science Center)

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Discovery	China	Peking University Health Science Center	-
Hepatocellular Carcinoma	Discovery	China	Beijing Cancer Hospital	-

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