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VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways

[ Vol. 20 , Issue. 8 ]

Author(s):

Jing-yi Sun, Ya-jun Hou, Hai-juan Cui, Cheng Zhang, Ming-feng Yang, Feng-ze Wang, Zheng Sun, Cun-dong Fan*, Bao-liang Sun* and Jin Rok Oh*Pages 616-623 (8)

Abstract:


Background: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity.

Objective: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells.

Methods: U2OS and MG-63 human osteosarcoma cells were cultured, and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential.

Results: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF.

Conclusion: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

Keywords:

VS-5584, osteosarcoma, G1-phase arrest, PI3K/mTOR, MAPK.

Affiliation:

Department of Orthopedics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26426, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Nursing, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, 261031, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Neurology, Second Affiliated Hospital; Key Lab of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, Department of Orthopedics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26426



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