Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells.
10.3858/emm.2012.44.4.019
- Author:
Ji Young JANG
1
;
Min Kyoung KIM
;
Yoon Kyung JEON
;
Yoon Ki JOUNG
;
Ki Dong PARK
;
Chul Woo KIM
Author Information
1. Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea. cwkim@snu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
ABCG2 protein, human;
adenine nucleotide translocator 2;
drug therapy, combination;
gene therapy;
neoplastic stem cells;
RNA, small interfering
- MeSH:
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
- From:Experimental & Molecular Medicine
2012;44(4):251-259
- CountryRepublic of Korea
- Language:English
-
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.
