title: d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway.
abstract: d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM) cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitorN-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.
authors.affiliation: Department of Developmental Cell Biology, Key Lab of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, College of Basic Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. zwmiao@cmu.edu.cn.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. fyu08@cmu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. yhren@cmu.edu.cn.
authors.forename: Yahao
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. jyang41@cmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013454:Sulfoxides
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D013454:Sulfoxides; C016766:sulforaphane
keywords: STAT3; apoptosis; glioblastoma multiforme; reactive oxygen species; sulforaphane