title: Downregulation of insulin-like growth factor-binding protein 7 in cisplatin-resistant non-small cell lung cancer.
abstract: Cisplatin is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLCs), but development of resistance is the primary impediment in cancer treatment. Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted tumor suppressor that is inactivated in human lung cancer. IGFBP7 is known to alter sensitivity to interferon-based anticancer therapy, and here, we examined loss of IGFBP7 as a potential contributor to chemo-resistance to cisplatin. The transcriptional level of IGFBP7 was decreased in cisplatin-resistant human cancer cell lines and NSCLC xenografts. IGFBP7 knock-down increased cellular resistance to cisplatin and increased the level of mitogen-activated protein kinase phosphatases (MKP) 3 levels. The expression of MKP3 increased in a cisplatin-resistant NSCLC cell line and lung xenografts. MKP3 knock-down increased IGFBP7 level, indicating that MKP3 regulates IGFBP7. These findings suggest a novel molecular mechanism responsible for the tumor suppressive function of IGFBP7 in cisplatin-resistant human lung cancer and could lead to the development of IGFBP7 as a cisplatin-sensitizing agent.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Okamura
authors.forename: Yiping
authors.initials: Y
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Moon
authors.forename: Mariana
authors.initials: M
authors.lastname: Brait
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chang
authors.forename: Myoung Sook
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D002945:Cisplatin