Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Balanagar, Hyderabad, 500037, A.P, India.
Apoptosis. 2014 Jul;19(7):1148-64. doi: 10.1007/s10495-014-0991-2.
The phosphatidylinositol 3-kinase (PI3 K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth and survival under physiological conditions. However, aberrant PI3 K/Akt/mTOR signaling has been implicated in many human cancers, including human triple negative breast cancer. Therefore, dual inhibitors of PI3 K/Akt and mTOR signaling could be valuable agents for treating breast cancer. The objective of this study was to investigate the effect of piperlongumine (PPLGM), a natural alkaloid on PI3 K/Akt/mTOR signaling, Akt mediated regulation of NF-kB and apoptosis evasion in human breast cancer cells. Using molecular docking studies, we found that PPLGM physically interacts with the conserved domain of PI3 K and mTOR kinases and the results were comparable with standard dual inhibitor PF04691502. Our results demonstrated that treatment of different human triple-negative breast cancer cells with PPLGM resulted in concentration- and time-dependent growth inhibition. The inhibition of cancer cell growth was associated with G1-phase cell cycle arrest and down-regulation of the NF-kB pathway leads to activation of the mitochondrial apoptotic pathway. It was also found that PPLGM significantly decreased the expression of p-Akt, p70S6K1, 4E-BP1, cyclin D1, Bcl-2, p53 and increased expression of Bax, cytochrome c in human triple-negative breast cancer cells. Although insulin treatment increased the phosphorylation of Akt (Ser473), p70S6K1, 4E-BP1, PPLGM abolished the insulin mediated phosphorylation, it clearly indicates that PPLGM acts through PI3 k/Akt/mTOR axis. Our results suggest that PPLGM may be an effective therapeutic agent for the treatment of human triple negative breast cancer.
磷脂酰肌醇 3-激酶 (PI3K)/Akt/哺乳动物雷帕霉素靶蛋白 (mTOR) 信号通路在生理条件下在细胞增殖、生长和存活中发挥核心作用。然而，异常的 PI3K/Akt/mTOR 信号已被牵连到许多人类癌症中，包括人三阴性乳腺癌。因此，PI3K/Akt 和 mTOR 信号的双重抑制剂可能是治疗乳腺癌的有价值的药物。本研究的目的是研究天然生物碱胡椒碱（PPLGM）对 PI3K/Akt/mTOR 信号、Akt 介导的 NF-kB 调节和细胞凋亡逃逸的影响在人类乳腺癌细胞中。通过分子对接研究，我们发现 PPLGM 与 PI3K 和 mTOR 激酶的保守结构域发生物理相互作用，结果与标准双重抑制剂 PF04691502 相当。我们的研究结果表明，用 PPLGM 处理不同的人三阴性乳腺癌细胞导致浓度和时间依赖性的生长抑制。癌细胞生长的抑制与 G1 期细胞周期停滞有关，NF-kB 途径的下调导致线粒体凋亡途径的激活。还发现 PPLGM 显著降低了人三阴性乳腺癌细胞中 p-Akt、p70S6K1、4E-BP1、细胞周期蛋白 D1、Bcl-2、p53 的表达，并增加了 Bax、细胞色素 c 的表达。尽管胰岛素处理增加了 Akt（Ser473）、p70S6K1、4E-BP1 的磷酸化，但 PPLGM 消除了胰岛素介导的磷酸化，这清楚地表明 PPLGM 通过 PI3K/Akt/mTOR 轴起作用。我们的研究结果表明，PPLGM 可能是治疗人三阴性乳腺癌的有效治疗药物。
