AKT phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer
AKT phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer
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DOI：
10.1002/ijc.21170
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发表时间：
2005-11-10
影响因子：
6.4
通讯作者：
Maehara, Y
中科院分区：
文献类型：
--
作者：
Oki, E;Baba, H;Maehara, Y
生长因子受体介导的信号转导与癌细胞对常规化疗的耐药有关。我们描述了一种涉及AKT/PI3K的途径来介导胃癌患者的化疗耐药。收集自1996~2000年在九州大学附属医院H外科手术的76例胃癌患者的原发胃癌组织和相应的正常胃粘膜。用磷酸化特异性抗体进行免疫染色检测AKT的活性，并在相同的样本中检测PTEN的杂合性缺失。22例(28.9%)胃癌组织中AKT磷酸化。AKT和磷酸化AKT与任何临床病理因素均无相关性。我们发现，AKT磷酸化(激活AKT)较高的胃癌患者似乎存在PTEN的LOH(p=0.0008)。当用四甲基偶氮唑盐比色法检测这些患者的化疗敏感性时，发现激活的AKT与对多种化疗药物(5-氟尿嘧啶、阿霉素、丝裂霉素C和顺铂)的耐药性增加有关。我们的研究结果表明，PTEN的AKT激活和杂合性缺失在胃癌患者产生广谱化疗耐药中起着重要作用。这也表明AKT可能因此成为一种新的分子靶点，用于改善胃癌患者的预后的治疗或化疗敏感性测试。(C)2005年Wiley-Liss，Inc.
Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery H in Kyushu University Hospital from the years 1996-2000. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p = 0.0008). When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents (5-fluorouracil, adriamycin, mitomycin C and cis-platinum). The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients. (c) 2005 Wiley-Liss, Inc.