title: PEITC induces apoptosis of Human Brain Glioblastoma GBM8401 Cells through the extrinsic- and intrinsic -signaling pathways.
abstract: Glioblastoma is the most common and most aggressive primary brain malignancy. The multimodality treatments for this tumor including surgery, radiotherapy, and chemotherapy, are still not completely satisfied. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, has been shown to induce apoptosis in many human cancer cells. In this study, we investigate the pro-apoptotic effects caused by PETIC in human brain glioblastoma multiforme GBM 8401 cells. In our data, PEITC induced the cell morphological changes and decreased the cell viability of GBM8401 cells in a dose- and time-dependent manner. Moreover, the analysis of cell cycle distribution detected by flow cytometry showed that PEITC induced significantly sub-G1 phase (apoptotic population) in GBM 8401 cells. In addition, PEITC promoted the production of reactive oxygen species (ROS) and increase in [Ca2+]I, but decreased the mitochondrial membrane potential (ΔΨm) in treated cells. PEITC also induced caspases activities in GBM 8401 cells. Results from Western blot analysis indicated that PEITC promoted Fas, FasL, FADD, TRAIL, caspase-8, -9, -3, increased the pro-apoptotic protein (Bax, Bid and Bak), and inhibited the anti-apoptotic proteins (Bcl-2 and Bcl-xl) in GBM 8401 cells. Furthermore, PEITC promoted the release of cytochrome c, AIF and Endo G. GADD153, GRP 78, XBP-1 and IRE-1α, Calpain I and II in GBM 8401 cells. PEITC also promoted the expression of associated protein with endoplasmic reticulum (ER) stress. PEITC induces apoptosis through the extrinsic (death receptor) pathway, dysfunction of mitochondria, ROS induced ER stress, intrinsic (mitochondrial) pathway in GBM 8401 cells. The possible molecular mechanisms and signaling pathways of the anti-cancer properties of PEITC for human brain glioblastoma cells were postulated.
authors.affiliation: Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung 407, Taiwan; Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan; School of Medicine, National Defense Medical Center, Taipei 114, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Meng-Ya
authors.initials: MY
authors.lastname: Chang
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Mei-Jen
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and College of Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Tomor
authors.initials: T
authors.lastname: Harnod
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Chih-Huang
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung 407, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.affiliation: Division of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors.forename: Chiung-Chyi
authors.initials: CC
authors.lastname: Shen
authors.affiliation: Departments of Biological Science and Technology, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: jgchung@mail.cmu.edu.tw.
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D002118:Calcium
keywords: Apoptosis; Caspases; Glioblastoma; Mitochondria; PEITC