title: A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells.
abstract: We recently showed that atypical protein kinase Ciota (PKCiota) is required for transformed growth of human non-small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCiota signaling blocks Rac1 activity and transformed growth, indicating that PKCiota is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer-based assay to identify inhibitors of oncogenic PKCiota signaling. This assay was used to identify compounds that disrupt the interaction between PKCiota and its downstream effector Par6, which links PKCiota to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKCiota-Par6 interactions in vitro (IC(50) approximately 1 micromol/L). ATG blocks PKCiota-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCiota and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKCiota for antitumor drug development and provide proof of concept that chemical disruption of PKCiota signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKCiota function in transformation and represent promising new agents for the clinical treatment of NSCLC.
authors.affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Stallings-Mann
authors.forename: Lee
authors.initials: L
authors.lastname: Jamieson
authors.forename: Roderick P
authors.initials: RP
authors.lastname: Regala
authors.forename: Capella
authors.initials: C
authors.lastname: Weems
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Murray
authors.forename: Alan P
authors.initials: AP
authors.lastname: Fields
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D006051:Aurothioglucose / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099293:Protein Kinase C-lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006051:Aurothioglucose; D002352:Carrier Proteins; D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D020830:rac1 GTP-Binding Protein; D000099293:Protein Kinase C-lambda; C499657:PARD6A protein, human; C107953:RAC1 protein, human