Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.
Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.
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DOI：
10.1038/bjc.2013.810
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发表时间：
2014-02-18
影响因子：
8.8
通讯作者：
Kolenko, V. M.
中科院分区：
文献类型：
--
作者：
Makhov, P.;Golovine, K.;Teper, E.;Kutikov, A.;Mehrazin, R.;Corcoran, A.;Tulin, A.;Uzzo, R. G.;Kolenko, V. M.
Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号传导途径是细胞生长、增殖和存活的关键调节因子。Akt异常激活与肿瘤发生和抗癌治疗耐药性有关。龙葵明（PL）是一种存在于长胡椒果实中的天然生物碱，已知具有显著的抗癌作用。在这里，我们研究PL对Akt/mTOR信号传导的影响。我们研究了PL治疗后各种来源的癌细胞（包括前列腺、肾脏和乳腺）中的Akt/mTOR信号传导。此外，评估了用PL和自噬抑制剂氯喹（CQ）伴随处理后的细胞活力。然后，我们使用小鼠异种移植肿瘤模型检查了体内组合治疗的功效。我们第一次证明PL有效地抑制了所有测试细胞中Akt靶蛋白的磷酸化。此外，Akt下游信号转导的下调导致mTORC 1活性和自噬刺激的降低。使用自噬抑制剂CQ，PL诱导的细胞死亡水平显著增加。此外，PL和CQ的伴随治疗在异种移植小鼠模型中显示出显著的抗肿瘤作用。我们的数据提供了使用PL介导癌症细胞死亡的新的治疗机会。因此，PL可能为预防和治疗恶性肿瘤提供新的范例。
The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling. We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model. We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model. Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.
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影响因子：
2.8
作者：
Ginzburg, Serge;Golovine, Konstantin V.;Makhov, Petr B.;Uzzo, Robert G.;Kutikov, Alexander;Kolenko, Vladimir M.
通讯作者：
Kolenko, Vladimir M.
影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
3.7
作者：
Hussain AR;Uddin S;Bu R;Khan OS;Ahmed SO;Ahmed M;Al-Kuraya KS
通讯作者：
Al-Kuraya KS
影响因子：
11.2
作者：
Apel, Anja;Herr, Ingrid;Mayer, Andreas
通讯作者：
Mayer, Andreas