title: Inhibition of IGF-IR increases chemosensitivity in human colorectal cancer cells through MRP-2 promoter suppression.
abstract: The emergence of multidrug resistance (MDR) in cancer cells has made many of the currently available chemotherapeutic agents ineffective. However, the mechanism involved in mediating this effect is not yet fully understood. Here, we found the overexpression of type I insulin-like growth factor receptor (IGF-IR) in established colorectal MDR cells. Specific siRNA of IGF-IR decreases cell proliferation, exert synergistic effect with anticancer drugs. The downstream signaling of IGF-IR, PI3K/AKT pathway, was altered upon IGF-IR silencing. The expression of multidrug-resistance-associated protein 2 (MRP-2) was suppressed due to the nuclear translocation of nuclear factor-like 2 (Nrf2). Then the intracellular drug concentration was increased and the drug-resistant phenotype was reversed. Our findings improve current understanding of the biology of IGF-IR and MDR and have significant therapeutic implications on colorectal MDR cancer.
authors.affiliation: State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Shen
authors.forename: Daling
authors.initials: D
authors.lastname: Cui
authors.forename: Liyun
authors.initials: L
authors.lastname: Sun
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Lu
authors.forename: Mingquan
authors.initials: M
authors.lastname: Han
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; C000715087:ABCC2 protein, human