Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death
Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death
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DOI：
10.1002/ijc.23049
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发表时间：
2008-01-15
影响因子：
6.4
通讯作者：
Yui, Jie-Ping
中科院分区：
文献类型：
--
作者：
Yu, Hong-Gang;Ai, Yao-Wei;Yui, Jie-Ping
胃癌成功治疗的主要障碍是化疗耐药性。我们的研究旨在探讨磷酸肌肽3-激酶(PI3K)/Akt通路在胃癌化疗耐药发展中的作用。在本研究中，28例胃癌组织中Akt表达和磷酸化（Ser 473）升高，PTEN表达降低。依托泊苷和阿霉素可刺激2种胃癌细胞株（BGC-823和SGC-7901）中Akt和PI3K的活性，且活性呈浓度和时间依赖性。瞬时转染PEAK8-PTEN后，上调BGC-823细胞中PTEN的表达，可明显降低基础药物和抗癌药物诱导的Akt活性，使BGC-823细胞对鲸泊苷和阿霉素增敏。用PI3K抑制剂wortmannin预处理BGC-823和SGC-7901细胞，可减弱细胞对依托泊苷和阿霉素的耐药性。此外，wortmannin预处理阻断了etoposide和阿霉素诱导ikappab - α降解，NFkappaB活化，Akt、MDM-2和叉头转录因子磷酸化。Wortmannin预处理也促进p27/Kip的积累，但抑制Mcl-1的表达。此外，wortmannin促进依托波苷和阿霉素诱导caspase-3、caspase-9活化和聚adp核糖聚合酶裂解。综上所述，这些观察结果表明PI3K/Akt通路在胃癌细胞的化疗耐药中起重要作用。我们应该设计一种新的胃癌联合化疗策略，更特异性地阻断PI3K/Akt通路，从而减少耐药细胞的数量。(C) 2007 Wiley-Liss, Inc。
The major obstacle to successful treatment of gastric cancer is chemotherapy resistance. Our study was designed to investigate the role of phosphoinositide 3-kinase (PI3K)/Akt pathway in the development of chemoresistance in gastric cancer. In the present study, elevated Akt expression and Akt phosphorylation (Ser 473), as well as decreased PTEN expression were observed in 28 cases of gastric cancer tissues. Etoposide and doxorubicin stimulated Akt and PI3K activities in 2 gastric cancer cell lines (BGC-823 and SGC-7901), and the activities were concentration and time-dependent. Up-regulation of PTEN expression in BGC-823 cells by PEAK8-PTEN transient transfection obviously decreased the basal and anticancer drugs induced Akt activities, then sensitized BGC-823 cells to etoposide and doxorubicin. Pretreatment of BGC-823 and SGC-7901 cells with wortmannin, a PI3K inhibitor, attenuated cells's resistance to etoposide and doxorubicin. In addition, pretreatment of wortmannin blocked etoposide and doxorubicin induced IkappaB-alpha degradation, NFkappaB activation, phosphorylation of Akt, MDM-2 and forkhead transcription factors. Wortmannin pretreatment also promoted the accumulation of p27/Kip, but inhibited the Mcl-1 expression. Furthermore, wortmannin promoted etoposide and doxorubicin induced caspase-3, caspase-9 activation and poly ADP-ribose polymerase cleavage. Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the chemoresistance of gastric cancer cells. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway and then decrease the amount of resistant cells. (C) 2007 Wiley-Liss, Inc.