Down-regulation of MSH2 expression by Hsp90 inhibition enhances cytotoxicity affected by tamoxifen in human lung cancer cells
Journal
Biochemical and Biophysical Research Communications
Journal Volume
456
Journal Issue
1
Pages
506-512
Date Issued
2015
Author(s)
Chiu H.-C.
Syu J.-J.
Chen C.-Y.
Jian Y.-T.
Huang Y.-J.
Wo T.-Y.
Jian Y.-J.
Chang P.-Y.
Wang T.-J.
Lin Y.-W.
Abstract
The anti-estrogen tamoxifen has been used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Human MutS homolog 2 (MSH2), a crucial element of the highly conserved DNA mismatch repair system, and expression of MSH2 have been down-regulated by Hsp90 function inhibition in human lung cancer. Therefore, in this study, we examined whether MSH2 plays a role in the tamoxifen and Hsp90 inhibitor-induced cytotoxic effect on NSCLC cells. The results showed that treatment with tamoxifen increased MSH2 mRNA and protein levels. The combination treatment with PI3K inhibitors (LY294002 or wortmannin) or knockdown AKT expression by specific small interfering RNA could decrease tamoxifen-induced MSH2 expression. Both knocking down MSH2 expression and co-treatment of PI3K inhibitors enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Compared to a single agent alone, tamoxifen combined with an Hsp90 inhibitor resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced MSH2 expression. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and Hsp90 inhibitors for the treatment of NSCLC. ? 2014 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
2 morpholino 8 phenylchromone; messenger RNA; protein; protein kinase B; protein MSH2; small interfering RNA; tamoxifen; tanespimycin; wortmannin; AKT1 protein, human; antineoplastic agent; heat shock protein 90; messenger RNA; MSH2 protein, human; protein kinase B; protein MSH2; small interfering RNA; tamoxifen; Article; cancer cell; cancer inhibition; cell growth; cell proliferation; cell survival; cell viability; controlled study; cytotoxicity; down regulation; drug mechanism; drug potentiation; enzyme inhibition; human; human cell; non small cell lung cancer; protein expression; Carcinoma, Non-Small-Cell Lung; down regulation; drug effects; gene expression profiling; gene expression regulation; genetic transfection; lung tumor; metabolism; tumor cell line; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; MutS Homolog 2 Protein; Proto-Oncogene Proteins c-akt; RNA, Messenger; RNA, Small Interfering; Tamoxifen; Transfection
Publisher
Academic Press Inc.
Type
journal article