REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

K. Kawasaki, Masami Watanabe, Masakiyo Sakaguchi, Y. Ogasawara, K. Ochiai, Yasutomo Nasu, Hiroyoshi Doihara, Y. Kashiwakura, N. H. Huh, H. Kumon, H. Date

Research output: Contribution to journalArticle

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Abstract

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

Original languageEnglish
Pages (from-to)65-72
Number of pages8
JournalCancer Gene Therapy
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 2009

Fingerprint

MCF-7 Cells
P-Glycoprotein
Down-Regulation
Apoptosis
Breast Neoplasms
Drug Resistance
Doxorubicin
Phosphotransferases
Therapeutics
Testicular Neoplasms
Multiple Drug Resistance
Tumor Suppressor Genes
Adenoviridae
Antineoplastic Agents
Neoplasms
Prostatic Neoplasms
Cell Death
Drug Therapy
Cell Line
Injections

Keywords

  • Apoptosis
  • Breast cancer
  • P-glycoprotein
  • REIC/Dkk-3

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer. / Kawasaki, K.; Watanabe, Masami; Sakaguchi, Masakiyo; Ogasawara, Y.; Ochiai, K.; Nasu, Yasutomo; Doihara, Hiroyoshi; Kashiwakura, Y.; Huh, N. H.; Kumon, H.; Date, H.

In: Cancer Gene Therapy, Vol. 16, No. 1, 01.2009, p. 65-72.

Research output: Contribution to journalArticle

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