title: Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking.
abstract: Glioblastoma is one of the most aggressive human cancers with poor prognosis, and therefore a critical need exists for novel therapeutic strategies for management of glioblastoma patients. Itraconazole, a traditional antifungal drug, has been identified as a novel potential anticancer agent due to its inhibitory effects on cell proliferation and tumor angiogenesis; however, the molecular mechanisms involved are still unclear. Here, we show that itraconazole inhibits the proliferation of glioblastoma cells both in vitro and in vivo. Notably, we demonstrate that treatment with itraconazole induces autophagic progression in glioblastoma cells, while blockage of autophagy markedly reverses the antiproliferative activities of itraconazole, suggesting an antitumor effect of autophagy in response to itraconazole treatment. Functional studies revealed that itraconazole retarded the trafficking of cholesterol from late endosomes and lysosomes to the plasma membrane by reducing the levels of SCP2, resulting in repression of AKT1-MTOR signaling, induction of autophagy, and finally inhibition of cell proliferation. Together, our studies provide new insights into the molecular mechanisms regarding the antitumor activities of itraconazole, and may further assist both the pharmacological investigation and rational use of itraconazole in potential clinical applications.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences; Chengdu Medical College; Chengdu, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences; Chengdu Medical College; Chengdu, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: College of Life Sciences; Sichuan University; Chengdu, China.
authors.forename: Linzhi
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Gastrointestinal Surgery; State Key Laboratory of Biotherapy; West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center; Chongqing Medical University; Chongqing, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Kefei
authors.initials: K
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: School of Medicine/Collaborative Innovation Center of Biotherapy; Nankai University; Tianjin, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Department of Biochemistry and Molecular Biology; Monash University; Clayton, Victoria Australia.
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
chemical_list: D002352:Carrier Proteins; C072087:sterol carrier proteins; D017964:Itraconazole; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: BECN1-PtdIns3K complex; antiproliferative; autophagy; cholesterol trafficking; itraconazole