Division of Cancer and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Center for Advanced Biomedical Science and Swine Research, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Hum Cell. 2020 Oct;33(4):1197-1203. doi: 10.1007/s13577-020-00416-9. Epub 2020 Aug 26.
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.
CD133 表达与胰腺癌预后不良和转移增加相关。CD133 阳性的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 CD133 细胞丰富的亚系作为胰腺 CSC 模型，并比较了双重 mTORC1/mTORC2 抑制剂 KU-0063794 与 mTORC1 特异性雷帕霉素的作用。我们发现 KU-0063794 在高浓度时可阻止球体形成，这是一个自我更新的指标。雷帕霉素抑制球体形成，但程度较轻。在本研究中，我们旨在确定 mTOR 复合物 2（mTORC2）在维持 CSC 样特性中的机制作用。通过检查 PI3K/Akt/mTOR 信号通路，我们观察到 KU-0063794 处理的细胞中 Akt 磷酸化水平降低。两种抑制剂均抑制了 mTORC1 下游效应物的磷酸化。因此，mTORC2 激活 Akt 并调节干细胞样特性，而 mTORC1 下游信号与干细胞样特性直接相关。
