Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2

Breeze E. Cavell, Sharifah S.Syed Alwi, Alison M. Donlevy, Christopher G. Proud, Graham Packham

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Phenethyl isothiocyanate (1) is a natural dietary phytochemical with cytostatic, cytotoxic, and antitumor activity. The effects of 1 were investigated on the activity of mTOR, a kinase that enhances the translation of many RNAs encoding proteins critical for cancer cell growth, including the angiogenesis regulator HIF1. Compound 1 effectively blocked HIF1 RNA translation in MCF7 breast cancer cells, and this was associated with reduced phosphorylation of 4E-BP1 and p70 S6K, wellcharacterized downstream substrates of the mTOR-containing mTORC1 complex. Compound 1 also inhibited mTORC1 activity in mouse embryonic fibroblasts (MEFs). The 1-mediated inhibition of mTORC1 activity appeared to be independent of the upstream regulators PTEN, AKT, ERK1/2, and AMPK. By contrast, 1-mediated inhibition of mTORC1 activity was dependent on the presence of TSC2, part of a complex that regulates mTORC1 activity negatively. TSC2-deficient MEFs were resistant to 1-mediated inhibition of p70 S6K phosphorylation. TSC2- deficient MEFs were also partially resistant to 1-mediated growth inhibition. Overall, the present results confirm that 1 inhibits mTORC1 activity. This is dependent on the presence of TSC2, and inhibition of mTORC1 contributes to optimal 1-induced growth inhibition. Inhibition of RNA translation may be an important component of the antitumor effects of phenethyl isothiocyanate.

Original languageEnglish
Pages (from-to)1051-1057
Number of pages7
JournalJournal of Natural Products
Volume75
Issue number6
DOIs
Publication statusPublished or Issued - 22 Jun 2012
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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