https://scholars.lib.ntu.edu.tw/handle/123456789/624349
標題: | Heat shock protein 90 inhibitor 17-AAG down-regulates thymidine phosphorylase expression and potentiates the cytotoxic effect of tamoxifen and erlotinib in human lung squamous carcinoma cells | 作者: | JEN-CHUNG KO Chen, Jyh-Cheng Hsieh, Jou-Min Tseng, Pei-Yu Chiang, Chen-Shan Liu, Li-Ling Chien, Chin-Cheng Huang, I-Hsiang Chang, Qiao-Zhen Mu, Bo-Cheng Lin, Yun-Wei |
關鍵字: | ERK1/2 mitogen-activated protein kinase; Erlotinib; Heat shock protein 90; Nonsmall cell lung cancer; Tamoxifen; Thymidine phosphorylase | 公開日期: | 十月-2022 | 出版社: | PERGAMON-ELSEVIER SCIENCE LTD | 卷: | 204 | 來源出版物: | Biochemical pharmacology | 摘要: | Elevated thymidine phosphorylase (TP) levels, a key enzyme in the pyrimidine nucleoside salvage pathway, in cancer cells, are related to a poor prognosis in a variety of cancers. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is involved in the stabilization and maturation of many oncogenic proteins. The aim of this study is to elucidate whether Hsp90 inhibitor 17-AAG could enhance tamoxifen- and erlotinib-induced cytotoxicity in nonsmall cell lung cancer (NSCLC) cells via modulating TP expression in two squamous NSCLC cell lines, H520 and H1703. We found that 17-AAG reduced TP expression via inactivating the MKK1/2-ERK1/2-mitogen-activated protein kinase (MAPK) pathway. TP knockdown with siRNA or ERK1/2 MAPK inactivation with the pharmacological inhibitor U0126 could enhance the cytotoxic and growth inhibitory effects of 17-AAG. In contrast, MKK1-CA or MKK2-CA (a constitutively active form of MKK1/2) vector-enforced expression could reduce the cytotoxic and cell growth inhibitory effects of 17-AAG. Furthermore, 17-AAG enhanced the cytotoxic and cell growth inhibitory effects of tamoxifen and erlotinib in NSCLC cells, which were associated with TP expression downregulation and MKK1/2-ERK1/2 signal inactivation. Taken together, Hsp90 inhibition downregulates TP, enhancing the tamoxifen- and erlotinib-induced cytotoxicity in H520 and H1703 cells. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/624349 | ISSN: | 0006-2952 | DOI: | 10.1016/j.bcp.2022.115207 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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