title: Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3.
abstract: Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells. When Akt was activated by genomic or pharmacologic approaches, IGFBP-3 transcription and protein stability were decreased. Conversely, suppression of Akt increased IGFBP-3 mRNA levels and protein stability in NSCLC cell lines. Characterization of the effects of constitutively active form of each Akt subtype (HA-Akt-DD) on IGFBP-3 expression in NSCLC cells and a xenograft model indicated that Akt3 plays a major role in the Akt-mediated regulation of IGFBP-3 expression and thus suppression of Akt effectively enhances the antitumor activities of IGFBP-3 in NSCLC cells with Akt3 overactivation. Collectively, these data suggest a novel function of Akt3 as a negative regulator of IGFBP-3, indicating the possible benefit of a combined inhibition of IGFBP-3 and Akt3 for the treatment of patients with NSCLC.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Quanri
authors.initials: Q
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John Kendal
authors.initials: JK
authors.lastname: Smith
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Whang
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-745, Republic of Korea and.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul 136-705, Republic of Korea.
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea, hylee135@snu.ac.kr.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt