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 journalArticlepeer-review

134 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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