Piperlongumine inhibits head and neck squamous cell carcinoma proliferation by docking to Akt
Piperlongumine inhibits head and neck squamous cell carcinoma proliferation by docking to Akt
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Piperlongumine 通过与 Akt 对接抑制头颈鳞状细胞癌增殖
DOI：
10.1002/ptr.6788
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发表时间：
2020-08-15
影响因子：
7.2
通讯作者：
Ji, Xu
中科院分区：
文献类型：
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作者：
Lv, Fei;Deng, Mingming;Ji, Xu
龙葵明（PL）是从长胡椒根中分离出的生物活性生物碱，广泛用作印度草药中的传统药物。然而，PL对头颈部鳞状细胞癌（HNSCC）的作用机制尚不清楚。我们进行细胞实验以证实PL对HNSCC的抑制作用，并使用顺铂作为阳性对照。其次，我们利用生物信息学方法预测了PL的潜在靶点，并通过蛋白质印迹法进行了验证。通过分子对接、Biacore实验和激酶活性测定等方法研究PL抑制靶点活性的机制。通过异种移植和免疫组织化学验证了体内功效。PL抑制HEp-2和FaDu细胞系的增殖，促进晚期凋亡，阻滞细胞周期并抑制DNA复制。利用生物信息学，我们发现PL的目标是Akt和PL减弱Akt磷酸化。通过分子对接、Biacore实验和激酶活性测定发现，PL通过与Akt对接抑制Akt的活性，从而抑制Akt的活化。此外，PL通过下调体内p-Akt的表达来显著抑制异种移植肿瘤的生长。本研究为PL的分子功能提供了新的见解，并表明其作为HNSCC治疗剂的潜力。
Piperlongumine (PL) is a biologically active alkaloid isolated from the long pepper roots and widely used as a traditional medicine in Ayurvedic medicine. However, the mechanism of PL's effect on head and neck squamous cell carcinoma (HNSCC) is not well understood. We performed cell experiments to confirm PL's inhibitory effect on HNSCC and employing cisplatin as positive control. Next, we conducted bioinformatics to predict PL's potential targets and verified by western blotting. Molecular docking, Biacore experiment and kinase activity assays were applied to elucidate the mechanism by which PL inhibited target activity. In vivo efficacy was verified by xenotransplantation and immunohistochemistry. PL inhibited proliferation, promoted late apoptosis, arrested cell cycle and inhibited DNA replication of the HEp‐2 and FaDu cell lines. Employing bioinformatics, we found that PL's target was Akt and PL attenuated Akt phosphorylation. We found from molecular docking, Biacore experiment and kinase activity assay that PL inhibited Akt activation by docking to Akt to restrain its activity. In addition, PL significantly inhibited the growth of xenograft tumors by down regulating the expression of p‐Akt in vivo. This study provides new insights into the molecular functions of PL and indicate its potential as a therapeutic agent for HNSCC.