title: NS1619 regulates the expression of caveolin-1 protein in a time-dependent manner via ROS/PI3K/PKB/FoxO1 signaling pathway in brain tumor microvascular endothelial cells.
abstract: NS1619, a calcium-activated potassium channel (Kca channel) activator, can selectively and time-dependently accelerate the formation of transport vesicles in both the brain tumor capillary endothelium and tumor cells within 15min of treatment and then increase the permeability of the blood-brain tumor barrier (BTB). However, the mechanism involved is still under investigation. Using a rat brain glioma (C6) model, the expression of caveolin-1, FoxO1 and p-FoxO1 protein were examined at different time points after intracarotid infusion of NS1619 at a dose of 30μg/kg/min. Internalization of Cholera toxin subunit (CTB) labeled fluorescently was monitored by flow cytometry. The expression of caveolin-1 and FoxO1 protein at tumor microvessels was enhanced and caveolae-mediated CTB endocytosis was increased by NS1619 infusion for 15min. Compared with the 15min group, the expression of caveolin-1 protein was significantly decreased and the level of phosphorylation of FoxO1 was significantly increased in the NS1619 2h group. In addition, inhibitors of reactive oxygen species (ROS) or PI3K or PKB significantly attenuated the level of FoxO1 phosphorylation and also increased the expression of caveolin-1 protein in Human Brain Microvascular Endothelial Cells (HBMECs) cocultured with human glioma cells (U87) 2h after NS1619 treatment. This led to the conclusion that NS1619-mediated transport vesicle increase is, at least partly, related to the ROS/PI3K/PKB/FoxO1 signaling pathway.
authors.affiliation: Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Cai
authors.affiliation: Department of Neurobiology, College Basic of Medicine, China Medical University, Shenyang, 110001, Liaoning Province, PR China.
authors.forename: Yi-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Department of Phytochemistry, Chinese Materia Medica Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Phytochemistry, Chinese Materia Medica Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Pharmacology Experiment Center, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Song-Yan
authors.initials: SY
authors.lastname: Zhao
authors.affiliation: Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Guan
authors.affiliation: Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China. Electronic address: zzhouzhang@163.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Life Science and Biopharmaceutical Institution, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China. Electronic address: yanting-gu@163.com.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Gu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000473:pathology; D002339:Carotid Arteries / Q000166:cytology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000473:pathology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D051242:Caveolin 1; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D017382:Reactive Oxygen Species; C086491:NS 1619; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002772:Cholera Toxin
keywords: Blood-brain tumor barrier; Caveolin-1; FoxO1; Glioma; NS1619