title: Resveratrol triggers ER stress-mediated apoptosis by disrupting N-linked glycosylation of proteins in ovarian cancer cells.
abstract: Malignant tumors have a high glucose demand and alter cellular metabolism to survive. Herein, focusing on the utility of glucose metabolism as a therapeutic target, we found that resveratrol induced endoplasmic reticulum (ER) stress-mediated apoptosis by interrupting protein glycosylation in a cancer-specific manner. Our results indicated that resveratrol suppressed the hexosamine biosynthetic pathway and interrupted protein glycosylation through GSK3β activation. Application of either biochemical intermediates of the hexosamine pathway or small molecular inhibitors of GSK3β reversed the effects of resveratrol on the disruption of protein glycosylation. Additionally, an ER UDPase, ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), modulated protein glycosylation by Akt attenuation in response to resveratrol. By inhibition or overexpression of Akt functions, we confirmed that the glycosylation activities were dependent on ENTPD5 expression and regulated by the action of Akt in ovarian cancer cells. Resveratrol-mediated disruption of protein glycosylation induced cellular apoptosis as indicated by the up-regulation of GADD153, followed by the activation of ER-stress sensors (PERK and ATF6α). Thus, our results provide novel insight into cancer cell metabolism and protein glycosylation as a therapeutic target for cancers.
authors.affiliation: Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Cancer Research Institute, Seoul National University, College of Medicine, Seoul 151-921, Republic of Korea.
authors.forename: HyeRan
authors.initials: H
authors.lastname: Gwak
authors.affiliation: Cancer Research Institute, Seoul National University, College of Medicine, Seoul 151-921, Republic of Korea; Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Soochi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Stephenson Cancer Center, Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Danny N
authors.initials: DN
authors.lastname: Dhanasekaran
authors.affiliation: Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Cancer Research Institute, Seoul National University, College of Medicine, Seoul 151-921, Republic of Korea; Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul National University, Seoul 151-921, Republic of Korea; Department of Obstetrics and Gynecology, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: yssong@snu.ac.kr.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Song
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006031:Glycosylation; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D013267:Stilbenes; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase; D038362:Glycogen Synthase Kinase 3; C117634:ENTPD5 protein, human; D011755:Pyrophosphatases; D000077185:Resveratrol
keywords: ER stress; Glucose metabolism; Glycosylation; Ovarian cancer; Resveratrol