This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, L.-Z. Articles by Jiang, B.-H. Search for Related Content PubMed PubMed Citation Articles by Liu, L.-Z. Articles by Jiang, B.-H.

AKT1 Amplification Regulates Cisplatin Resistance in Human Lung Cancer Cells through the Mammalian Target of Rapamycin/p70S6K1 Pathway

¹ Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China; ² Institute of Respiratory Diseases, Xinqiao Hospital and ³ Department of Respiratory Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China; ⁴ Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and ⁵ Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia

Requests for reprints: Bing-Hua Jiang, Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu, China. E-mail: bhjiang{at}njmu.edu.cn.

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 play 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. [Cancer Res 2007;67(13):6325–32]

This article has been cited by other articles:

				J. M. McDonald, C. E. Pelloski, A. Ledoux, M. Sun, G. Raso, R. Komaki, I. I. Wistuba, B. N. Bekele, and K. Aldape Elevated Phospho-S6 Expression Is Associated with Metastasis in Adenocarcinoma of the Lung Clin. Cancer Res., December 1, 2008; 14(23): 7832 - 7837. [Abstract] [Full Text] [PDF]

				S. Fernandez de Mattos, P. Villalonga, J. Clardy, and E. W-F. Lam FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells Mol. Cancer Ther., October 1, 2008; 7(10): 3237 - 3246. [Abstract] [Full Text] [PDF]

				N. Eckstein, K. Servan, L. Girard, D. Cai, G. von Jonquieres, U. Jaehde, M. U. Kassack, A. F. Gazdar, J. D. Minna, and H.-D. Royer Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells J. Biol. Chem., January 11, 2008; 283(2): 739 - 750. [Abstract] [Full Text] [PDF]