The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423.
The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423.
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发表时间：
2010-02
影响因子：
3.1
通讯作者：
Hisashi Hashimoto;Tamotsu Sudo;Hiroshi Maruta;Ryuichiro Nishimura
中科院分区：
文献类型：
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作者：
Hisashi Hashimoto;Tamotsu Sudo;Hiroshi Maruta;Ryuichiro Nishimura
到目前为止，还没有开发出有效的治疗方法用于FDA批准的卵巢癌患者的治疗。最近，我们提供了第一个证据，表明称为伊维菌素的旧抗生素（抗寄生虫药物）通过某种方式使致癌激酶PAK 1失活而在体外抑制多种人卵巢癌细胞系的生长（Hashimoto H等人，Drug Discov Ther. 2009;3：243-246）。现在已知这种激酶对于超过70%的所有人类癌症的生长是必需的，所述癌症包括乳腺癌、前列腺癌、胰腺癌、结肠癌、胃癌、肺癌、宫颈癌、甲状腺癌以及肝癌、神经胶质瘤、黑素瘤、MM（多发性骨髓瘤）和NF（神经纤维瘤病）肿瘤。在本研究中，使用阻断必需的PAK 1-PIX相互作用的细胞可渗透的PAK 1失活肽TAT-PAK 18，我们检查了卵巢癌细胞系对这种抗PAK 1肽的敏感性与这些细胞系中PAK 1的蛋白表达/自磷酸化水平之间的关系，发现PAK 1异常激活越多，（在Thr 423处自磷酸化），它们的生长对该肽越敏感，而不管它们的PAK 1表达水平如何。这一观察结果提供了第一个直接证据，表明卵巢癌也属于PAK 1依赖性癌症，占所有人类癌症的70%以上，这表明抗PAK 1药物将是卵巢癌的有效治疗方法。
So far no effective therapeutic has been developed for the FDA-approved treatment of ovarian cancer patients. Recently we provided the first evidence indicating that an old antibiotic (antiparasitic drug) called Ivermectin suppresses the growth of a variety of human ovarian cancer cell lines in vitro by inactivating the oncogenic kinase PAK1 somehow (Hashimoto H, et al. Drug Discov Ther. 2009;3:243-246). This kinase is now known to be essential for the growth of more than 70% of all human cancers including breast, prostate, pancreatic, colon, gastric, lung, cervical, thyroid cancers as well as hepatoma, glioma, melanoma, MM (multiple myeloma) and NF (neurofibromatosis) tumors. In this study, using the cell-permeable PAK1-inactivating peptide TAT-PAK18 which blocks the essential PAK1-PIX interaction, we examined the relationship between the sensitivity of ovarian cancer cell lines to this anti-PAK1 peptide and the protein expression/autophosphorylation levels of PAK1 in these cell lines, and found that the more PAK1 is abnormally activated (autophosporylated at Thr 423), the more their growth is sensitive to this peptide, regardless of their PAK1 expression levels. This observation provides the first direct evidence that ovarian cancers also belong to the PAK1-dependent cancers which represent more than 70% of all human cancers, suggesting that anti-PAK1 drugs would be effective therapeutics for ovarian cancers.