The isothiocyanate sulforaphane inhibits mTOR in an NRF2-independent manner

Ying Zhang, Amy Gilmour, Young-Hoon Ahn, Laureano de la Vega, Albena Dinkova-Kostova (Lead / Corresponding author)

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Abstract

Background: The isothiocyanate sulforaphane (SFN) has multiple protein targets in mammalian cells, affecting processes of fundamental importance for the maintenance of cellular homeostasis, among which are those regulated by the stress response transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) and the serine/threonine protein kinase mechanistic target of rapamycin (mTOR). Whereas the way by which SFN activates NRF2 is well established, the molecular mechanism(s) of how SFN inhibits mTOR is not understood.

Hypothesis/Purpose: The aim of this study was to investigate the mechanism(s) by which SFN inhibits mTOR.

Study Design and Methods: We used the human osteosarcoma cell line U2OS and its CRISPR/Cas9-generated NRF2-knockout counterpart to test the requirement for NRF2 and the involvement of mTOR regulators in the SFN-mediated inhibition of mTOR.

Results: SFN inhibits mTOR in a concentration- and time-dependent manner, and this inhibition occurs in the presence or in the absence of NRF2. The phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) is a positive regulator of mTOR, and treatment with SFN caused an increase in the phosphorylation of AKT at T308 and S473, two phosphorylation sites associated with AKT activation. Interestingly however, the levels of pS552 β-catenin, an AKT phosphorylation site, were decreased, suggesting that the catalytic activity of AKT was inhibited. In addition, SFN inhibited the activity of the cytoplasmic histone deacetylase 6 (HDAC6), the inhibition of which has been reported to promote the acetylation and decreases the kinase activity of AKT.

Conclusion: SFN inhibits HDAC6 and decreases the catalytic activity of AKT, and this partially explains the mechanism by which SFN inhibits mTOR.
Original languageEnglish
Article number153062
JournalPhytomedicine
Early online date5 Aug 2019
DOIs
Publication statusE-pub ahead of print - 5 Aug 2019

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Keywords

  • HDAC6
  • mTOR
  • NRF2
  • PI3K-AKT
  • sulforaphane
  • Sulforaphane

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