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Blockade of STAT3 Signaling Contributes to Anticancer Effect of 5-Acetyloxy-6,7,8,4′-Tetra-Methoxyflavone, a Tangeretin Derivative, on Human Glioblastoma Multiforme Cells

1
Division of Neurosurgery, Department of Surgery, Yuanlin Changhua Christian Hospital, Changhua 50006, Taiwan
2
Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan
3
Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal University, Huanggang 438000, China
4
Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
5
Transplant Medicine & Surgery Research Center, Changhua Christian Hospital, Changhua 50006, Taiwan
6
Department of Anesthesiology, Tungs’ Taichung MetroHarbor Hospital, Taichung 43503, Taiwan
7
Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
8
Department of Life Sciences, The iEGG and Animal Biotechnology Research Center, Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
9
Department of Biotechnology, Asia University, Taichung 41354, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(13), 3366; https://doi.org/10.3390/ijms20133366
Received: 30 May 2019 / Revised: 4 July 2019 / Accepted: 7 July 2019 / Published: 9 July 2019
(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)
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Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4′-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment. View Full-Text
Keywords: glioblastoma multiforme; STAT3; tangeretin; 5-acetyloxy-6,7,8,4′-tetramethoxyflavone; polymethoxyflavone; BCL-2; BCL-xL; apoptosis glioblastoma multiforme; STAT3; tangeretin; 5-acetyloxy-6,7,8,4′-tetramethoxyflavone; polymethoxyflavone; BCL-2; BCL-xL; apoptosis
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Cheng, Y.-P.; Li, S.; Chuang, W.-L.; Li, C.-H.; Chen, G.-J.; Chang, C.-C.; Or, C.-H.R.; Lin, P.-Y.; Chang, C.-C. Blockade of STAT3 Signaling Contributes to Anticancer Effect of 5-Acetyloxy-6,7,8,4′-Tetra-Methoxyflavone, a Tangeretin Derivative, on Human Glioblastoma Multiforme Cells. Int. J. Mol. Sci. 2019, 20, 3366.

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