The class I PI3K/Akt pathway is critical for cancer cell survival in dogs and offers an opportunity for therapeutic intervention.
The class I PI3K/Akt pathway is critical for cancer cell survival in dogs and offers an opportunity for therapeutic intervention.
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DOI：
10.1186/1746-6148-8-73
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发表时间：
2012-05-30
影响因子：
2.6
通讯作者：
Argyle DJ
中科院分区：
文献类型：
--
作者：
Chen YT;Tan KA;Pang LY;Argyle DJ
利用新型小分子抑制剂，我们探索了I型PI3K/Akt/mTORC1信号通路作为犬肿瘤治疗靶点的可行性，无论是单独使用途径抑制剂，还是与常规化疗药物联合使用。我们证明所测试的细胞系的生长和存活主要依赖于I类PI3K/Akt信号而不是mTORC1信号。此外，新开发的分别针对PAN-I类PI3K和Akt的抑制剂ZSTK474和KP372-1，以及已经被公认为高度特异的mTOR抑制剂的雷帕霉素，降低了犬癌细胞系的存活率。所有的抑制剂都表现出对通路成员磷酸化的抑制。Annexin V染色显示KP372-1是一种强有力的细胞凋亡诱导剂，而ZSTK474和雷帕霉素则是较弱的诱导剂。ZSTK474与雷帕霉素联合抑制I类PI3K和mTORC1后，细胞存活率降低，而PI3K途径抑制剂与常规药物阿霉素联合应用时的反应依赖于细胞系。这项研究强调了I类PI3K/Akt轴信号在犬肿瘤细胞中的重要性，并将其确定为一个有前景的治疗靶点。
Using novel small-molecular inhibitors, we explored the feasibility of the class I PI3K/Akt/mTORC1 signaling pathway as a therapeutic target in canine oncology either by using pathway inhibitors alone, in combination or combined with conventional chemotherapeutic drugs in vitro. We demonstrate that growth and survival of the cell lines tested are predominantly dependent on class I PI3K/Akt signaling rather than mTORC1 signaling. In addition, the newly developed inhibitors ZSTK474 and KP372-1 which selectively target pan-class I PI3K and Akt, respectively, and Rapamycin which has been well-established as highly specific mTOR inhibitor, decrease viability of canine cancer cell lines. All inhibitors demonstrated inhibition of phosphorylation of pathway members. Annexin V staining demonstrated that KP372-1 is a potent inducer of apoptosis whereas ZSTK474 and Rapamycin are weaker inducers of apoptosis. Simultaneous inhibition of class I PI3K and mTORC1 by ZSTK474 combined with Rapamycin additively or synergistically reduced cell viability whereas responses to the PI3K pathway inhibitors in combination with conventional drug Doxorubicin were cell line-dependent. This study highlighted the importance of class I PI3K/Akt axis signaling in canine tumour cells and identifies it as a promising therapeutic target.