title: Oroxylin A induces autophagy in human malignant glioma cells via the mTOR-STAT3-Notch signaling pathway.
abstract: Autophagy is a tightly-regulated catabolic pathway involving degradation of cellular proteins, cytoplasm and organelles. Recent evidence suggests that autophagy plays a potential role in cell death as a tumor suppressor and that its induction especially in combination with apoptosis could be beneficial. It remains unclear if all cancer cells behave the same mechanism when autophagy is induced. Although mammalian target of rapamycin (mTOR) is well known as a negative regulator of autophagy, the relationship between signal transducer and activator of transcription 3 (STAT3) and autophagy has not yet been investigated. Oroxylin A, a natural mono-flavonoid extracted from Scutellariae radix, is a promising therapeutic agent for treating multiple cancers. Here we investigated the mechanism underlying the effect of oroxylin A on malignant glioma cells. We showed that oroxylin A inhibited the proliferation of malignant glioma cells by inducing autophagy in a dose- and time-dependent manner. Oroxylin A treatment inhibits the AKT and ERK activation and the downstream phosphorylation level of mTOR and STAT3. In addition, oroxylin A treatment decreases the expression of Notch-1 and myeloid cell leukemia-1 (Mcl-1) but upregulates Beclin 1, the key autophagy-related protein. 3-MA (autophagy inhibitor) or knockdown of Beclin 1 partially can rescue cells from oroxylin A-induced autophagic cell death. In contrast, knockdown of STAT3 aggravates oroxylin A-induced autophagic cell death. Our data reveal an important role of autophagy in enhancing cell death induced by oroxylin A and conclude that oroxylin A exerts anti-malignant glioma proficiency by inducing autophagy via the ERK/AKT-mTOR-STAT3-Notch signaling cascade.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zou
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.affiliation: School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Aixia
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D005419:Flavonoids; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: autophagy; cell death; mTOR-STAT3-Notch; malignant glioma cells; oroxylin A