title: Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
abstract: Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine-Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
authors: Joshua E
authors: JE
authors: Allen
authors: Gabriel
authors: G
authors: Krigsfeld
authors: Patrick A
authors: PA
authors: Mayes
authors: Luv
authors: L
authors: Patel
authors: David T
authors: DT
authors: Dicker
authors: Akshal S
authors: AS
authors: Patel
authors: Nathan G
authors: NG
authors: Dolloff
authors: Evangelos
authors: E
authors: Messaris
authors: Kimberly A
authors: KA
authors: Scata
authors: Wenge
authors: W
authors: Wang
authors: Jun-Ying
authors: JY
authors: Zhou
authors: Gen Sheng
authors: GS
authors: Wu
authors: Wafik S
authors: WS
authors: El-Deiry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D024201:Bystander Effect / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles; D051379:Mice; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C585684:TIC10 compound; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
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