AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway
AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway
复制标题
DOI：
10.1158/0008-5472.can-06-4261
复制
发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Jiang, Bing-Hua
中科院分区：
文献类型：
--
作者：
Liu, Ling-Zhi;Zhou, Xiang-Dong;Jiang, Bing-Hua
顺铂[顺-二氨基二氯铂（CDDP）]是治疗多种癌症最广泛、最有效的药物之一。然而，由于耐药性的发展，其效率受到限制。在本研究中，我们发现在获得耐药的人肺癌细胞中，CDDP耐药与AKT1过表达和基因扩增有关。我们发现，AKT1在细胞中的强制表达足以使细胞对CDDP产生抗性，并且AKT1的显性阴性突变体抑制了CDDP抗性细胞，使其对CDDP敏感。这些结果表明，AKT1的活性对调节培养的肺癌细胞的CDDP抗性至关重要。为了研究这些结果是否与人肺癌肿瘤相关，我们随机选取人肺癌患者的肿瘤样本，研究临床肿瘤样本中AKT活化与CDDP耐药的相关性。我们发现AKT激活与人肿瘤组织中CDDP的化学敏感性高度相关。我们的研究结果进一步表明，AKT1通过雷帕霉素（mTOR）信号通路的哺乳动物靶点诱导肺癌细胞对CDDP产生耐药性。这些研究表明，AKT扩增和mTOR通路在人肺癌细胞获得CDDP耐药过程中发挥了重要作用，这代表了一种获得CDDP耐药的新机制，也是未来人类癌症克服CDDP耐药的潜在新治疗靶点。
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.