title: Down-regulation of MSH2 expression by Hsp90 inhibition enhances cytotoxicity affected by tamoxifen in human lung cancer cells.
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.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan.
authors.forename: Jen-Chung
authors.initials: JC
authors.lastname: Ko
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Hsien-Chun
authors.initials: HC
authors.lastname: Chiu
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Jhan-Jhang
authors.initials: JJ
authors.lastname: Syu
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yun-Ting
authors.initials: YT
authors.lastname: Jian
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yi-Jhen
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Wo
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Jian
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
authors.forename: Tai-Jing
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan. Electronic address: linyw@mail.ncyu.edu.tw.
authors.forename: Yun-Wei
authors.initials: YW
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013629:Tamoxifen; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: AKT; Hsp90 inhibition; MSH2; Non-small cell lung cancer; Tamoxifen