HSP90 inhibition induces cytotoxicity via down-regulation of Rad51 expression and DNA repair capacity in non-small cell lung cancer cells
Journal
Regulatory Toxicology and Pharmacology
Journal Volume
64
Journal Issue
3
Pages
415-424
Date Issued
2012
Author(s)
Chen H.-J.
Huang Y.-C.
Tseng S.-C.
Weng S.-H.
Wo T.-Y.
Huang Y.-J.
Chiu H.-C.
Tsai M.-S.
Chiou R.Y.Y.
Lin Y.-W.
Abstract
Heat shock protein 90 (HSP90) is an exciting new target in cancer therapy. Repair protein Rad51 is involved in protecting non-small cell lung cancer (NSCLC) cell lines against chemotherapeutic agent-induced cytotoxicity. This study investigated the role of Rad51 expression in HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced cytotoxicity in two NSCLC cell lines, A549 and H1975. The 17-AAG treatment decreased cellular Rad51 protein and mRNA levels and phosphorylated MKK1/2-ERK1/2 protein levels, and disrupted the HSP90 and Rad51 interaction. This triggered Rad51 protein degradation through the 26S proteasome pathway. The 17-AAG treatment also decreased the NSCLC cells’ DNA repair capacity, which was restored by the forced expression of the Flag-Rad51 vector. Specific inhibition of Rad51 expression by siRNA further enhanced 17-AAG-induced cytotoxicity. In contrast, enhanced ERK1/2 activation by the constitutively active MKK1/2 (MKK1/2-CA) vector significantly restored the 17-AAG-reduced Rad51 protein levels and cell viability. Arachidin-1, an antioxidant stilbenoid, further decreased Rad51 expression and augmented the cytotoxic effect and growth inhibition of 17-AAG. The 17-AAG and arachidin-1-induced synergistic cytotoxic effects and decreased DNA repair capacity were abrogated in lung cancer cells with MKK1/2-CA or Flag-Rad51 expression vector transfection. In conclusion, HSP90 inhibition induces cytotoxicity by down-regulating Rad51 expression and DNA repair capacity in NSCLC cells. ? 2012 Elsevier Inc.
SDGs
Other Subjects
26S proteasome; antioxidant; arachidin 1; heat shock protein 90; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; proteasome; Rad51 protein; tanespimycin; unclassified drug; antineoplastic agent; arachidin 1; arachidin-1; benzoquinone derivative; heat shock protein 90; macrocyclic lactam; messenger RNA; Rad51 protein; RAD51 protein, human; small interfering RNA; stilbene derivative; tanespimycin; A-549 cell line; Article; cancer inhibition; controlled study; DNA repair; dose time effect relation; down regulation; drug cytotoxicity; drug potentiation; human; human cell; lung cancer cell line; NCI-H1975 cell line; priority journal; protein degradation; protein phosphorylation; protein protein interaction; article; cell survival; DNA repair; drug antagonism; drug effect; gene expression regulation; genetics; lung non small cell cancer; lung tumor; metabolism; pathology; tumor cell line; Antineoplastic Agents; Benzoquinones; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; DNA Repair; Down-Regulation; Drug Synergism; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lung Neoplasms; Rad51 Recombinase; RNA, Messenger; RNA, Small Interfering; Stilbenes
Publisher
Academic Press Inc.
Type
journal article