title: Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2.
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.
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, SO16 6YD, UK.
authors.forename: Breeze E
authors.initials: BE
authors.lastname: Cavell
authors.forename: Sharifah S
authors.initials: SS
authors.lastname: Syed Alwi
authors.forename: Alison M
authors.initials: AM
authors.lastname: Donlevy
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D015151:Immunoblotting; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D015394:Molecular Structure; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017879:Isothiocyanates; D046912:Multiprotein Complexes; D011506:Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C058305:phenethyl isothiocyanate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases