Abstract A85: Mutant P53 as a potential target of chemopreventive isothiocyanates
| Autor: | Emily Greenspan, York Tomita, Lixin Mi, Anthony DiPasqua, Xiantao Wang, Fung-Lung Chung |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 10:A85-A85 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.targ-11-a85 |
| Popis: | Studies in animals and humans support isothiocyanates (ITCs) as a promising class of cancer chemopreventive agents. It is believed that apoptosis induction and cell cycle arrest are important mechanisms underlying their chemopreventive effects. While several signaling pathways have been shown to be associated with their activities, little is known about the molecular targets of ITCs until recent years. Evidence obtained in this study supports a role of mutant p53 as a potential target of ITCs. We showed ITCs can selectively deplete mutant p53, but not the wild type, in various human cancer cells in a structure-dependent manner, as phenethyl ITC (PEITC) and benyl ITC (BITC) are potent mutant p53 depletors, whereas sulforaphane (SFN) is not. The SAR studies showed 2,2-diphenyl ITC, a synthetic compound, is the most potent mutant p53 depletor. We found the potencies of depletion coincide with their mutant p53 binding affinities, providing circumstantial evidence for a mechanism involving its direct binding by ITCs. The depletion of mutant p53 in cells by ITCs appears to involve protein aggregation. Nine pairs of isogenic cells with mutant p53 and shRNA knockdown were generated. Overall, cells with mutant p53 appear to grow faster than the corresponding cells with mutant p53 knockdown, consistent with its role in gain-of-function. However, no significant difference was noted in PEITC-induced apoptosis between the cell pairs examined so far, suggesting targets other than mutant p53 in these cancer cells may also be involved. DNA array studies using PEITC-treated SW480 colon cancer cells provide potential new lead targets. Furthermore, the role of mutant p53 depletion in preventing lung carcinogenesis by ITCs is also examined in mutant p53 transgenic animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A85. |
| Databáze: | OpenAIRE |
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