Suppr超能文献

PI3K/Akt 致癌通路的调节剂影响人腺癌细胞中的 mTOR 复合物 2。

Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells.

机构信息

College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA, 30341, USA.

出版信息

Invest New Drugs. 2019 Oct;37(5):902-911. doi: 10.1007/s10637-018-0705-7. Epub 2018 Dec 13.

Abstract

Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.

摘要

鞘氨醇酮 K(ChK)是一种天然产物,已被证明能促进 F-肌动蛋白加帽、抑制生长、阻断细胞周期 G2 期并诱导细胞凋亡。ChK 还被证明能下调参与致癌途径的两种重要激酶,Akt 和 JNK。本报告研究了 ChK 如何参与受体酪氨酸激酶途径(RTK/PI3K/mTORC2/Akt)到位于中央的蛋白激酶 Akt。研究报告称,ChK 不像渥曼青霉素那样抑制 PI3K,也不影响 PDK1 的激活。PDK1 负责 Akt T308 的磷酸化,而 mTORC2 磷酸化 Akt S473。然而,Akt 的两个激活位点 T308 和 S473 已知受 ChK 处理的影响。我们的假设是 ChK 作用于 mTORC2 复合物,抑制 Akt S473 的磷酸化。这种在 mTORC2 上的抑制作用应该会降低 Akt 和 mTORC2 复合物这两种蛋白质的磷酸化,与已知的 mTOR 特异性抑制剂 Torin1 相比。用人肺腺癌细胞 H1299 和 H2009 用 IGF-1 或 calyculin A 处理以增加 mTORC2 和 Akt 的磷酸化。用 ChK 预处理能够显著降低与 IGF-1 或 calyculin A 处理相似的 Akt S473 的磷酸化。此外,mTORC2 复合物的自身磷酸化位点 S2481 也随着 ChK 预处理而显著减少,与 Torin1 相似。这是第一个表明 ChK 对 mTORC2 S2481 和 Akt S473 有显著影响的报告,与 Torin1 相当,表明它可能是一种 mTOR 抑制剂。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验