Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer.
Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer.
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DOI：
10.18632/oncotarget.3139
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发表时间：
2015-04-10
期刊：
影响因子：
--
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Liu Z;He W;Gao J;Luo J;Huang X;Gao C
PIM蛋白家族是短命的丝氨酸/苏氨酸激酶(PIM1、PIM2和PIM3)，是弱癌基因，但作为肿瘤靶点与肿瘤的发生有关。因此，设计一种新型的PAN-PIM抑制剂仍然是当前癌症药物开发的一个挑战。在这里，我们使用朴素贝叶斯模型来构建PIM网络，并确定Bad和Hsp90与PIM相互作用。然后，我们筛选了一系列靶向PIMs的候选小分子化合物，并随后合成了具有显著抗宫颈癌细胞增殖活性的新型小分子化合物PI003。此外，我们还发现，PI003通过靶向PIMs，影响Bad和Hsp90，通过死亡受体和线粒体途径诱导细胞凋亡。结合microRNA芯片分析，我们发现miR-1296和miR-1299等microRNAs在PI003诱导的细胞凋亡中可能影响PIM1-STAT3通路。最后，我们报道了PI003在小鼠体内模型中具有显著的抗肿瘤活性和诱导细胞凋亡的作用。综上所述，这些结果表明PI003作为一种新的合成的PAN-PIM抑制剂，能够诱导参与microRNA调控的死亡受体和线粒体的凋亡，并且在体内也具有显著的抗肿瘤活性和诱导凋亡的作用。因此，这些发现将有助于在未来的宫颈癌治疗中发现更多潜在的新的小分子PAN-PIM抑制剂。
PIM protein family, short-lived serine/threonine kinases (PIM1, PIM2 and PIM3), are weak oncogenes but contribute to tumorigenesis as cancer targets. Thus, design of a novel pan-PIM inhibitor is still a challenge for current cancer drug discovery. Herein, we used a Naïve Bayesian model to construct the PIM network and identified Bad and Hsp90 to interact with PIMs. Then, we screened a series of candidate small-molecule compounds targeting PIMs, and subsequently synthesized a novel small-molecule compound PI003 with remarkable anti-proliferative activities in cervical cancer cells. Moreover, we found that PI003 induced apoptosis via the death-receptor and mitochondrial pathways by targeting PIMs and affecting Bad and Hsp90. Combined with microRNA microarray analyses, we demonstrated that some microRNAs such as miR-1296 and miR-1299 could affect PIM1-STAT3 pathway in PI003-induced apoptosis. Finally, we reported that PI003 had remarkable anti-tumor activity and apoptosis-inducing effect in in vivo mouse model. In conclusion, these results demonstrate that PI003, as a novel synthesized pan-PIM inhibitor, induces the death-receptor and mitochondrial apoptosis involved in microRNA regulation, and also possessed remarkable anti-tumor activity and apoptosis-inducing effect in vivo. Thus, these findings would shed light on discovering more potential new small-molecule pan-PIM inhibitors in future cervical cancer therapy.
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