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

摘要: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer Activator Transcription 3 (STAT3) evidenced as a pivotal driver GBM pathogenesis therapy resistance, hence, promising drug target. 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF) an acetylated derivative Tangeretin which known exert anticancer effects on breast, colon, lung, multiple myeloma; however, its effect remains elusive. Herein, we reported that 5-AcTMF suppressed viability clonogenicity along inducing apoptosis in human cell lines. Mechanistic analyses further revealed lowered levels Tyrosine 705-phosphorylated STAT3 (p-STAT3), canonical marker activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression dominant-active impeded 5-AcTMF-induced suppression plus induction cells, confirming prerequisite blockage for inhibitory action survival growth. Additionally, impaired upstream kinase JAK2 downregulated antiapoptotic BCL-2 BCL-xL STAT3-dependent manner. Moreover, overexpression either or abrogated 5-AcTMF-mediated reduction cells. Collectively, we, first time, was executed via thwarting JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings implicate therapeutic potential treatment.