Calcium channel α2δ1 subunit is a functional marker and therapeutic target for tumor-initiating cells in non-small cell lung cancer

Cell Death Dis. 2021 Mar 11;12(3):257. doi: 10.1038/s41419-021-03522-0.

Abstract

It is hypothesized that tumor-initiating cells (TICs) with stem cell-like properties constitute a sustaining force to drive tumor growth and renew fully established malignancy. However, the identification of such a population in non-small cell lung carcinoma (NSCLC) has been hindered by the lacking of reliable surface markers, and very few of the currently available surface markers are of functional significance. Here, we demonstrate that a subpopulation of TICs could be specifically defined by the voltage-gated calcium channel α2δ1 subunit from non-small cell lung carcinoma (NSCLC) cell lines and clinical specimens. The α2δ1+ NSCLC TICs are refractory to conventional chemotherapy, and own stem cell-like properties such as self-renewal, and the ability to generate heterogeneous tumors in NOD/SCID mice. Moreover, α2δ1+ NSCLC cells are more enriched for TICs than CD133+, or CD166+ cells. Interestingly, α2δ1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx into cells, which subsequently activate Calcineurin/NFATc2 signaling that directly activates the expression of NOTCH3, ABCG2. Importantly, a specific antibody against α2δ1 has remarkably therapeutic effects on NSCLC xenografts by eradicating TICs. Hence, targeting α2δ1 to prevent calcium influx provides a novel strategy for targeted therapy against TICs of NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents, Immunological / pharmacology
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Calcineurin / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation
  • Cell Self Renewal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Receptor, Notch3 / genetics
  • Receptor, Notch3 / metabolism
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • CACNA2D1 protein, human
  • Calcium Channel Blockers
  • Calcium Channels
  • NFATC Transcription Factors
  • NFATC2 protein, human
  • NOTCH3 protein, human
  • Neoplasm Proteins
  • Receptor, Notch3
  • Calcineurin