AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway

被引:174
|
作者
Liu, Ling-Zhi
Zhou, Xiang-Dong
Qian, Guisheng
Shi, Xianglin
Fang, Jing
Jiang, Bing-Hua [1 ]
机构
[1] Nanjing Med Univ, Ctr Canc, Nanjing 210029, Jiangsu, Peoples R China
[2] Xinqiao Hosp, Inst Resp Dis, Chongqing, Peoples R China
[3] Third Mil Med Univ, Dept Resp Dis, Southwest Hosp, Chongqing, Peoples R China
[4] Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China
[5] W Virginia Univ, Mary Babb Randolph Canc Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA
关键词
D O I
10.1158/0008-5472.CAN-06-4261
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is one of the most widely used and effective therapeutic agents for many kinds of cancers. However, its efficiency is limited due to development of drug resistance. In this study, we showed that CDDP resistance was associated with AKT1 overexpression and gene amplification in human lung cancer cells that acquired the drug resistance. We showed that AKT1 forced expression in the cells was sufficient to render the cells CDDP resistant, and that AKT1 inhibition by its dominant negative mutant reversed the CDDP-resistant cells to be CDDP sensitive. These results show that AKT1 activity is essential for regulating CDDP resistance in cultured lung cancer cells. To study whether these results were correlated with human lung cancer tumors, we randomly selected tumor samples from human lung cancer patients to study the correlation of AKT activation and CDDP resistance in clinical tumor samples. We showed that AKT activation was highly related to CDDP chemosensitivity in human tumor tissues. Our results further showed that AKT1 induced lung cancer cells to become resistant to CDDP through the mammalian target of the rapamycin (mTOR) signaling pathway. These studies conclude that AKT amplification and the mTOR pathway p ay an important role in human lung cancer cells acquiring CDDP resistance, which represents a new mechanism for acquiring CDDP resistance and a potential novel therapeutic target for overcoming CDDP resistance in human cancer in the future.
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页码:6325 / 6332
页数:8
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