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

Abstract

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 a2d1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of a2d1-mediated chemoresistance and strategies of overcoming the resistance. Experimental Design: a2d1-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 a2d1mediated chemoresistance in SCLC. In addition, possible interventions to overcome a2d1-mediated chemoresistance were examined. Results: Different proportions of a2d1 þ cells were identified in SCLC cell lines and PDX models. a2d1 þ cells exhibited CSClike properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of a2d1 þ cells instead of CD133 þ cells in PDXs, and an increased proportion of a2d1 þ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the a2d1-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 a2d1 demonstrated CSClike properties, and may contribute to chemoresistance. ERK may play a key role in a2d1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. Ó2018 AACR.

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

“…This mechanism might be involved in the maintenance of CSC property and resistance to chemotherapy. 10 , 27 In the NSCLC cell lines in this study, the increased phosphorylation level of ATM, rapid decrease in γH2AX after radiation and upregulation of DNA damage repair gene RAD51 in the CACNA2D1 -overexpressing cell line or α2δ1-high cells suggests that α2δ1 might enhance radioresistance by imparting a more efficient capacity to repair DNA damage.…”

Evaluation of diagnostic accuracy of serum calcium channel α2δ1 subunit in hepatocellular carcinoma-related cirrhosis

“…Many studies showed an expression of α2δ1 subunit in different types of malignancies such as pancreatic [21], ovarian [22], and lung tumors [14] and demonstrated a potential resistance to chemotherapy and may carry bad prognosis. Han et al as well identified a subpopulation of TICs expressing α2δ1 subunit, which is essential for the activation of calcium influx that controls the TIC ability of HCC by an antibody against Hep-12 cells [23].…”

“…Other authors showed that there were other types of cancer that contain α2δ1+ cells such as small-cell lung cancer, laryngeal squamous cell carcinoma, and gastric cancer, with nearly the same stem cell-like properties [12], resistant to chemotherapy [13], and overexpression of ERK1/2 [14]. Also, they showed that inhibition of α2δ1 may serve as a new promising therapeutic target for these CSCs [15,16].…”

The Cancer Stem Cell in Hepatocellular Carcinoma

“…Other types of cancer also contain a subset of α2δ1+ cells (small-cell lung cancer, laryngeal squamous cell carcinoma and gastric cancer), showing not only the same stem cell-like properties [197], but also the same chemoresistant phenotype [198] and overexpression of ERK1/2 [199]. In all cases, inhibition of α2δ1 has been proposed as a new promising therapeutic target for CSCs, including HCC CSCs [197][198][199][200].…”