Exp Mol Med.  2012 Apr;44(4):251-259. 10.3858/emm.2012.44.4.019.

Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells

Affiliations
  • 1Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea. cwkim@snu.ac.kr
  • 2Center for Biomaterials, Korea Institute of Science and Technology, Seoul 136-791, Korea.
  • 3Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.

Abstract

Cancer stem cells (CSCs) are resistant to chemo- and radio-therapy, and can survive to regenerate new tumors. This is an important reason why various anti-cancer therapies often fail to completely control tumors, although they kill and eliminate the bulk of cancer cells. In this study, we determined whether or not adenine nucleotide translocator-2 (ANT2) suppression could also be effective in inducing cell death of breast cancer stem-like cells. A sub-population (SP; CD44+/CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. We utilized the adeno-ANT2 shRNA virus to inhibit ANT2 expression and then observed the treatment effect in a SP of breast cancer cell line. In this study, MCF7, MDA-MB-231 cells, and breast epithelial cells (MCF10A) mesenchymally-transdifferentiated through E-cadherin knockdown were used. ANT2 expression was high in both stem-like cells and non-stem-like cells of MCF7 and MDA-MB-231 cells, and was induced and up-regulated by mesenchymal transdifferentiation in MCF10A cells (MCF10AEMT). Knockdown of ANT2 by adeno-shRNA virus efficiently induced apoptotic cell death in the stem-like cells of MCF7 and MDA-MB-231 cells, and MCF10AEMT. Stem-like cells of MCF7 and MDA-MB-231, and MCF10AEMT cells exhibited increased drug (doxorubicin) resistance, and expressed a multi-drug resistant related molecule, ABCG2, at a high level. Adeno-ANT2 shRNA virus markedly sensitized the stem-like cells of MCF7 and MDA-MB-231, and the MCF10AEMT cells to doxorubicin, which was accompanied by down-regulation of ABCG2. Our results suggest that ANT2 suppression by adeno-shRNA virus is an effective strategy to induce cell death and increase the chemosensitivity of stem-like cells in breast cancer.

Keyword

ABCG2 protein, human; adenine nucleotide translocator 2; drug therapy, combination; gene therapy; neoplastic stem cells; RNA, small interfering

MeSH Terms

ATP-Binding Cassette Transporters/*genetics/metabolism
Adenine Nucleotide Translocator 2/antagonists & inhibitors/genetics
Adenoviridae/*genetics
Antineoplastic Agents/pharmacology
Apoptosis/drug effects/genetics
Breast Neoplasms
Cadherins/antagonists & inhibitors/genetics
Cell Line, Tumor
Cell Survival/drug effects/genetics
Cell Transdifferentiation/drug effects
Doxorubicin/pharmacology
Drug Resistance, Neoplasm/drug effects/*genetics
Epithelial-Mesenchymal Transition/drug effects
Female
Gene Expression Regulation, Neoplastic/drug effects
Gene Knockdown Techniques
Humans
Neoplasm Proteins/*genetics/metabolism
Neoplastic Stem Cells/drug effects/*metabolism/pathology
RNA, Small Interfering/*genetics
Signal Transduction/drug effects
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