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|Title:||Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2|
|Citation:||Journal of Natural Products, 2012; 75(6):1051-1057|
|Publisher:||American Chemical Society|
|Breeze E. Cavell, Sharifah S. Syed Alwi, Alison M. Donlevy, Christopher G. Proud, and Graham Packham|
|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 HIF1α. Compound 1 effectively blocked HIF1α RNA translation in MCF7 breast cancer cells, and this was associated with reduced phosphorylation of 4E-BP1 and p70 S6K, well-characterized 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.|
|Keywords:||Fibroblasts; Animals; Humans; Mice; Isothiocyanates; Multiprotein Complexes; Proteins; Tumor Suppressor Proteins; Antineoplastic Agents; Immunoblotting; Molecular Structure; Female; Hypoxia-Inducible Factor 1, alpha Subunit; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Tuberous Sclerosis Complex 2 Protein|
|Rights:||© 2012 American Chemical Society and American Society of Pharmacognosy|
|Appears in Collections:||Molecular and Biomedical Science publications|
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