Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth
Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth
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DOI：
10.1038/sj.onc.1208744
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发表时间：
2005-09-08
期刊：
影响因子：
8
通讯作者：
Testa, JR
中科院分区：
文献类型：
--
作者：
Altomare, DA;You, HH;Testa, JR
恶性间皮瘤(MMS)是一种侵袭性很强的肿瘤，对标准的化疗方法反应很差。磷脂酰肌醇3-激酶(PI3K)/AKT通路与肿瘤的侵袭性有关，部分是通过调节细胞存活和降低对化疗的敏感性。使用识别磷酸化/激活形式的AKT激酶的抗体，我们在26例人类MM标本中观察到17例磷酸化AKT染色升高(65%)。此外，在石棉处理的小鼠的MMS和MM细胞异种移植中持续观察到AKT的磷酸化。与涉及MM中肝细胞生长因子(HGF)/Met受体信号转导的报道一致，所有14个人和小鼠MM细胞系都具有HGF诱导的AKT活性。在9个人MM细胞系中，有一个在血清饥饿条件下AKT活性升高，这与PTEN纯合缺失有关，这在MM中是首次报道。用mTOR抑制剂雷帕霉素处理该细胞系后，该细胞株的生长停滞在G1期。PI3K抑制剂LY294002与顺铂联合作用于MM细胞后，其抑制细胞增殖和诱导细胞凋亡的作用明显优于单独使用任何一种药物。总之，这些数据表明，MMS经常表达升高的AKT活性，这可能是药理学上的靶向，以提高化疗疗效。这些发现还表明，多发性骨髓瘤小鼠模型可能对未来针对PI3K/AKT通路的药物的临床前研究有用。
Malignant mesotheliomas ( MMs) are very aggressive tumors that respond poorly to standard chemotherapeutic approaches. The phosphatidylinositol 3- kinase ( PI3K)/AKT pathway has been implicated in tumor aggressiveness, in part by mediating cell survival and reducing sensitivity to chemotherapy. Using antibodies recognizing the phosphorylated/activated form of AKT kinases, we observed elevated phospho-AKT staining in 17 of 26 ( 65%) human MM specimens. In addition, AKT phosphorylation was consistently observed in MMs arising in asbestos-treated mice and in MM cell xenografts. Consistent with reports implicating hepatocyte growth factor (HGF)/Met receptor signaling in MM, all 14 human and murine MM cell lines had HGF- inducible AKT activity. One of nine human MM cell lines had elevated AKT activity under serum-starvation conditions, which was associated with a homozygous deletion of PTEN, the first reported in MM. Treatment of this cell line with the mTOR inhibitor rapamycin resulted in growth arrest in G1 phase. Treatment of MM cells with the PI3K inhibitor LY294002 in combination with cisplatin had greater efficacy in inhibiting cell proliferation and inducing apoptosis than either agent alone. Collectively, these data indicate that MMs frequently express elevated AKT activity, which may be targeted pharmacologically to enhance chemotherapeutic efficacy. These findings also suggest that mouse models of MM maybe useful for future preclinical studies of pharmaceuticals targeting the PI3K/AKT pathway.