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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Zhongyu Liu1,*, Weihua He1,*, Jianglin Gao1, Junhua Luo2, Xian Huang1, Chunfang Gao1
1Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China
2Department of Obstetrics & Gynecology, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China
*These authors have contributed equally to this work
Chunfang Gao, e-mail: [email protected]
Keywords: PIM kinase family, Pan-PIM inhibitor (PI003), HeLa cell, Apoptosis, MicroRNA
Received: December 20, 2014 Accepted: January 10, 2015 Published: February 04, 2015
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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