Molecular mechanism of down-regulation of MSH2 expression by Hsp90 inhibitors to enhance cytotoxicity of tamoxifen in human squamous cell lung carcinoma

• Main Authors: Jhan-Jhang, Syu, 許展彰
• Other Authors: Yun-Wei, Lin
• Format: Others
• Language: en_US
• Online Access: http://ndltd.ncl.edu.tw/handle/32173685965868881468

碩士 === 國立嘉義大學 === 生化科技學系研究所 === 103 === The anti-estrogen tamoxifen has been used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, clinical studies has show that tamoxifen-induced cytotoxicity also occurred in non-small cell lung cancer (NSCLC) cells. However the molecular mechanism has not been identified. Human MutS homolog 2 (MSH2), a crucial element of the highly conserved DNA mismatch repair system, plays an important role in preserving genetic stability, the expression of MSH2 has been down-regulated by Hsp90 inhibition in human lung cancer. Hsp90, a molecular chaperone, can assist protein folding to restore its normal function. 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 (0.5–10 µM) increased MSH2 mRNA and protein levels in an AKT-dependent manner. Furthermore, combination treatment with PI3K inhibitors (LY294002 or wortmannin) or knockdown AKT expression by specific small interfering RNA could decrease tamoxifen-induced MSH2 expression in H1703 cells. Knocking down MSH2 expression and co-treatment with PI3K inhibitors (LY294002 or wortmannin) enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Compared to a single agent, tamoxifen combined with an Hsp90 inhibitor resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced MSH2 mRNA and protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and Hsp90 inhibitors for the treatment of NSCLC.