title: 17-Allylamino-17-Demethoxygeldanamycin and the Enhancement of PS-341-Induced Lung Cancer Cell Death by Blocking the NF-κB and PI3K/Akt Pathways.
abstract: PS-341 is a highly selective and potent proteasome inhibitor that is cytotoxic to various types of cancer. However, no objective response was seen in a clinical trial with PS-341 as a single agent in non-small cell lung cancer. Its antitumor activity is limited by the simultaneously activated antiapoptosis pathway. Recently, PS-341-induced NF-κB activation via IκBα degradation has been suggested to be one of its antiapoptotic effects. In this study, we investigated the effects of a combined application of the heat shock protein (Hsp) 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) with PS-341 in lung cancer cells. Hsp90 inhibition with 17-AAG was effective in enhancing PS-341-induced lung cancer cell death in vitro and in vivo. 17-AAG pretreatment induced the degradation of upstream regulators of IκB, IL-1R-associated kinase-1 (IRAK-1), and IκB kinases (IKKs), dose and time dependently, which resulted in blocking of PS-341-induced IκBα degradation, p65 nuclear translocation, transcriptional activity, and NF-κB-regulated antiapoptotic gene expressions such as COX-2. The concentrations of 17-AAG used for combinatorial treatment with PS-341 did not change cell viability or the activity of proteasome complex. Moreover, 17-AAG pretreatment decreased the level of phsophorylated Akt at serine 473 residue and suppressed active Akt-dependent inactivation of glycogen synthase kinase 3β. 17-AAG mediated the dissociation of its client proteins (IRAK-1, IKKs, and Akt) from the Hsp90 complex. As a result, it induced degradation of target proteins. Our results suggest that the combination of 17-AAG and PS-341 could be an effective anticancer therapy that overcomes the limited effects of PS-341.
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Medical Research Center, Seoul National University College of Medicine, Seoul South Korea.
authors: Kyoung-Hee
authors: KH
authors: Lee
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Medical Research Center, Seoul National University College of Medicine, Seoul South Korea.
authors: An-Hee
authors: AH
authors: Jang
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Medical Research Center, Seoul National University College of Medicine, Seoul South Korea.
authors: Chul-Gyu
authors: CG
authors: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; C112765:tanespimycin; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase
keywords: 17-AAG; Akt; GSK-3β; NF-κB; PS-341