Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition
Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition
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DOI：
10.1007/s13577-020-00416-9
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发表时间：
2020-08-26
期刊：
影响因子：
4.3
通讯作者：
Takao, Sonshin
中科院分区：
文献类型：
--
作者：
Matsubara, Shyuichiro;Tsukasa, Koichiro;Takao, Sonshin
胰腺癌中CD 133表达与预后不良和转移增加相关。CD 133（+）胰腺癌细胞表现出癌症干细胞（CSC）样特性。我们从Capan-1胰腺癌细胞中建立了一个富含CD 133（+）细胞的亚系作为胰腺CSC模型，并比较了KU-0063794（一种mTORC 1/mTORC 2双重抑制剂）与mTORC 1特异性雷帕霉素的作用。我们发现，KU-0063794在高浓度下可防止球体形成，这是一种自我更新指数。雷帕霉素抑制球体形成，但程度较低。在本研究中，我们的目的是确定mTOR复合物2（mTORC 2）在维持CSC样特性中的机制作用。通过检查PI 3 K/Akt/mTOR信号通路，我们观察到KU-0063794处理的细胞中Akt磷酸化较低。两种抑制剂均抑制mTORC 1下游效应物的磷酸化。因此，mTORC 2激活Akt并调节干细胞样特性，而mTORC 1下游信号传导与干细胞样特性直接相关。
CD133 expression in pancreatic cancer correlates with poor prognosis and increased metastasis. CD133(+)pancreatic cancer cells exhibit cancer stem cell (CSC)-like properties. We established a CD133(+)cell-rich subline from Capan-1 pancreatic cancer cells as a pancreatic CSC model and compared the effects of KU-0063794, a dual mTORC1/mTORC2 inhibitor, against those of mTORC1-specific rapamycin. We found that KU-0063794 prevents sphere formation, a self-renewal index, at high concentrations. Rapamycin inhibited sphere formation but to a lesser degree. In the present study, we aimed to determine the mechanistic roles of mTOR complex 2 (mTORC2) in maintaining CSC-like properties. By examining the PI3K/Akt/mTOR signaling pathway, we observed lower Akt phosphorylation in KU-0063794-treated cells. Phosphorylation of mTORC1 downstream effectors was inhibited by both inhibitors. Thus, mTORC2 activates Akt and modulate stem-like properties, whereas mTORC1 downstream signaling correlates directly with stem-like properties.