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https://hdl.handle.net/2440/95849
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Type: | Journal article |
Title: | Natural product-derived antitumor compound phenethyl isothiocyanate inhibits mTORC1 activity via TSC2 |
Author: | Cavell, B. Alwi, S. Donlevy, A. Proud, C. Packham, G. |
Citation: | Journal of Natural Products, 2012; 75(6):1051-1057 |
Publisher: | American Chemical Society |
Issue Date: | 2012 |
ISSN: | 0163-3864 1520-6025 |
Statement of Responsibility: | 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 |
DOI: | 10.1021/np300049b |
Published version: | http://dx.doi.org/10.1021/np300049b |
Appears in Collections: | Aurora harvest 3 Molecular and Biomedical Science publications |
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