Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Wang,Jian; Liu,Ke; Wang,Xiao-Feng; Sun,Dian-Jun

doi:10.3892/or.2017.5878

Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis

Authors:
- Jian Wang
- Ke Liu
- Xiao-Feng Wang
- Dian-Jun Sun
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Affiliations: Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China, Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province and Ministry of Health, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: August 3, 2017 https://doi.org/10.3892/or.2017.5878
Pages: 1959-1966
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Accumulating data show that prolylisomerase (Pin1) is overexpressed in human glioblastoma multiforme (GBM) specimens. Therefore, Pin1 inhibitors should be investigated as a new chemotherapeutic drug that may enhance the clinical management of human gliomas. Recently, juglone, a Pin1 inhibitor, was shown to exhibit potent anticancer activity in various tumor cells, but its role in human glioma cells remains unknown. In the present study, we determined if juglone exerts antitumor effects in the U251 human glioma cell line and investigated its potential underlying molecular mechanisms. Cell survival, apoptosis, migration, angiogenesis and molecular targets were identified with multiple detection techniques including the MTT cell proliferation assay, dual acridine orange/ethidium bromide staining, electron microscopy, transwell migration assay, chick chorioallantoic membrane assay, quantitative real-time polymerase chain reaction and immunoblotting. The results showed that 5-20 µM juglone markedly suppressed cell proliferation, induced apoptosis, and enhanced caspase-3 activity in U251 cells in a dose- and time-dependent manner. Moreover, juglone inhibited cell migration and the formation of new blood vessels. At the molecular level, juglone markedly suppressed Pin1 levels in a time-dependent manner. TGF-β1/Smad signaling, a critical upstream regulator of miR-21, was also suppressed by juglone. Moreover, the transient overexpression of Pin1 reversed its antitumor effects in U251 cells and inhibited juglone-mediated changes to the TGF-β1/miR-21 signaling pathway. These findings suggest that juglone inhibits cell growth by causing apoptosis, thereby inhibiting the migration of U251 glioma cells and disrupting angiogenesis; and that Pin1 is a critical target for juglone's antitumor activity. The present study provides evidence that juglone has in vitro efficacy against glioma. Therefore, additional studies are warranted to examine the clinical potential of juglone in human gliomas.

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