Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Department of Ophthalmology, The Fourth People's Hospital of Shenyang, Shenyang, Liaoning 110001, P.R. China.
Int J Mol Med. 2018 Apr;41(4):2099-2107. doi: 10.3892/ijmm.2018.3398. Epub 2018 Jan 18.
Mammalian target of rapamycin (mTOR) serves a central role in regulating cell growth and survival, and has been demonstrated to be involved in the pathological progression of posterior capsule opacification (PCO). In the present study, the potency of PP242, a novel dual inhibitor of mTOR complex 1/2 (mTORC1/2), in the suppression of the growth of human lens epithelial cells (HLECs) was investigated. Using a Cell Counting Kit‑8 and a wound healing assay, it was demonstrated that PP242 inhibited the proliferation and migration of HLECs. In addition, western blot analysis indicated that PP242 completely inhibited mTORC1 and mTORC2 downstream signaling activities, whereas rapamycin only partially inhibited mTORC1 activity within LECs. Furthermore, PP242 treatment led to an upregulation of the expression levels of p53 and B cell lymphoma‑2 (Bcl‑2)‑associated X and downregulation of Bcl‑2. In addition, flow cytometric analysis demonstrated that PP242 induced the cell cycle arrest at the G0/G1 phase, which may have caused apoptosis and induced autophagy within the LECs. The results of the present study suggested that administration of PP242 may potentially offer a novel therapeutic approach for the prevention of PCO.
哺乳动物雷帕霉素靶蛋白（mTOR）在调节细胞生长和存活方面发挥着核心作用，并且已经证明其参与了后囊膜混浊（PCO）的病理进展。在本研究中，研究了新型 mTOR 复合物 1/2（mTORC1/2）双重抑制剂 PP242 抑制人晶状体上皮细胞（HLEC）生长的能力。使用细胞计数试剂盒-8 和划痕愈合试验表明，PP242 抑制了 HLEC 的增殖和迁移。此外，Western blot 分析表明，PP242 完全抑制了 mTORC1 和 mTORC2 下游信号转导活性，而雷帕霉素仅部分抑制了 LEC 中的 mTORC1 活性。此外，PP242 处理导致 p53 和 B 细胞淋巴瘤-2（Bcl-2）相关 X 上调和 Bcl-2 下调。此外，流式细胞术分析表明，PP242 诱导 LEC 中的细胞周期停滞在 G0/G1 期，这可能导致细胞凋亡并诱导自噬。本研究的结果表明，PP242 的给药可能为预防 PCO 提供一种新的治疗方法。
