title: Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.
abstract: Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.
authors.affiliation: Department of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Jurriaan
authors.initials: J
authors.lastname: Brouwer-Visser
authors.affiliation: Department of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: KellyAnne
authors.initials: K
authors.lastname: McCullagh
authors.affiliation: Department of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Cossio
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology & Women's Health (Division of Gynecologic Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Huang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C035170:IGF2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D017239:Paclitaxel