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

Cavell, Breeze E., Syed Alwi, Sharifah S., Donlevy, Alison M., Proud, Christopher G. and Packham, Graham (2012) Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2. Journal of Natural Products, 75 (6), 1051-1057. (doi:10.1021/np300049b). (PMID:22607231)

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, 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.

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Contributors

Author: Graham Packham

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