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

International Journal of Molecular Sciences

Chia-Hsuan Li¹  Ping-Yi Lin²  Yen-Po Cheng³  Shiming Li⁴  Guan-Jun Chen⁵  Ching-Chin Chang⁵  Chi-HungR. Or⁵  Wan-Ling Chuang⁶  Chia-Che Chang⁶ 

[1] Surgery Research Center, Changhua Christian Hospital, Changhua 50006, Taiwan;Department of Anesthesiology, Tungs’ Taichung MetroHarbor Hospital, Taichung 43503, Taiwan;Division of Neurosurgery, Department of Surgery, Yuanlin Changhua Christian Hospital, Changhua 50006, Taiwan;Hubei Key Laboratory for Processing and Application of Catalytic Materials, Huanggang Normal University, Huanggang 438000, China;Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan;;Transplant Medicine &

关键词: glioblastoma multiforme;    STAT3;    tangeretin;    5-acetyloxy-6,7,8,4′-tetramethoxyflavone;    polymethoxyflavone;    BCL-2;    BCL-xL;    apoptosis;   

DOI  :  10.3390/ijms20133366

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown