Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects

Joshua E. Allen, Gabriel Krigsfeld, Patrick A. Mayes, Luv Patel, David T. Dicker, Akshal S. Patel, Nathan G. Dolloff, Evangelos Messaris, Kimberly A. Scata, Wenge Wang, Jun Ying Zhou, Gen Sheng Wu, Wafik S. El-Deiry

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number171ra17
JournalScience Translational Medicine
Volume5
Issue number171
DOIs
StatePublished - Feb 6 2013

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Extracellular Signal-Regulated MAP Kinases
Genes
Up-Regulation
Cellular Microenvironment
Neoplasms
Blood-Brain Barrier
Antineoplastic Agents
Half-Life
Phosphotransferases
Tumor Necrosis Factor-alpha
TIC10 compound
Clinical Trials
Apoptosis
Ligands
Costs and Cost Analysis
Drug Therapy
Brain
Serum
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Allen, Joshua E. ; Krigsfeld, Gabriel ; Mayes, Patrick A. ; Patel, Luv ; Dicker, David T. ; Patel, Akshal S. ; Dolloff, Nathan G. ; Messaris, Evangelos ; Scata, Kimberly A. ; Wang, Wenge ; Zhou, Jun Ying ; Wu, Gen Sheng ; El-Deiry, Wafik S. / Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. In: Science Translational Medicine. 2013 ; Vol. 5, No. 171.
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Allen, JE, Krigsfeld, G, Mayes, PA, Patel, L, Dicker, DT, Patel, AS, Dolloff, NG, Messaris, E, Scata, KA, Wang, W, Zhou, JY, Wu, GS & El-Deiry, WS 2013, 'Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects', Science Translational Medicine, vol. 5, no. 171, 171ra17. https://doi.org/10.1126/scitranslmed.3004828

Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. / Allen, Joshua E.; Krigsfeld, Gabriel; Mayes, Patrick A.; Patel, Luv; Dicker, David T.; Patel, Akshal S.; Dolloff, Nathan G.; Messaris, Evangelos; Scata, Kimberly A.; Wang, Wenge; Zhou, Jun Ying; Wu, Gen Sheng; El-Deiry, Wafik S.

In: Science Translational Medicine, Vol. 5, No. 171, 171ra17, 06.02.2013.

Research output: Contribution to journalArticle

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AU - Zhou, Jun Ying

AU - Wu, Gen Sheng

AU - El-Deiry, Wafik S.

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