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Cited by 101Cancer-related Molecular PathwaysGenomics, phytochemicals, and oxidative stressHeat shock proteins research

Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth

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Aggarwal, M, Saxena, R, Sinclair, E, Fu, Y, Jacobs, A, Dyba, M, Wang, X, Cruz, I +7 more·2016·Cell Death & Differentiation
DOI 10.1038/cdd.2016.48PMC PMC5041190
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Abstract

Mutations in the p53 tumor-suppressor gene are prevalent in human cancers. The majority of p53 mutations are missense, which can be classified into contact mutations (that directly disrupts the DNA-binding activity of p53) and structural mutations (that disrupts the conformation of p53). Both of the mutations can disable the normal wild-type (WT) p53 activities. Nevertheless, it has been amply documented that small molecules can rescue activity from mutant p53 by restoring WT tumor-suppressive functions. These compounds hold promise for cancer therapy and have now entered clinical trials. In this study, we show that cruciferous-vegetable-derived phenethyl isothiocyanate (PEITC) can reactivate p53 mutant under in vitro and in vivo conditions, revealing a new mechanism of action for a dietary-related compound. PEITC exhibits growth-inhibitory activity in cells expressing p53 mutants with preferential activity toward p53(R175), one of the most frequent 'hotspot' mutations within the p53 sequence. Mechanistic studies revealed that PEITC induces apoptosis in a p53(R175) mutant-dependent manner by restoring p53 WT conformation and transactivation functions. Accordingly, in PEITC-treated cells the reactivated p53(R175) mutant induces apoptosis by activating canonical WT p53 targets, inducing a delay in S and G2/M phase, and by phosphorylating ATM/CHK2. Interestingly, the growth-inhibitory effects of PEITC depend on the redox state of the cell. Further, PEITC treatments render the p53(R175) mutant sensitive to degradation by the proteasome and autophagy in a concentration-dependent manner. PEITC-induced reactivation of p53(R175) and its subsequent sensitivity to the degradation pathways likely contribute to its anticancer activities. We further show that dietary supplementation of PEITC is able to reactivate WT activity in vivo as well, inhibiting tumor growth in xenograft mouse model. These findings provide the first example of mutant p53 reactivation by a dietary compound and have important implications for cancer prevention and therapy.

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  • Dietary compound PEITC can reactivate p53 mutants in vitro and in vivo and preferentially demonstrated growth-inhibitory activity in p53-R175H versus p53-R273H and p53-R248Q tumor cells.

    “Dietary compound PEITC can reactivate p53 mutants in vitro and in vivo and preferentially demonstrated growth-inhibitory activity in p53-R175H vs. p53-R273H and p53-R248Q tumor cells [133].”

    From The p53 Pathway in Glioblastoma (2018) · cites this paper as [133]

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Authors
Aggarwal, M., Saxena, R., Sinclair, E., Fu, Y., Jacobs, A., Dyba, M., Wang, X., Cruz, I., Berry, D., Kallakury, B., Mueller, S. C., Agostino, S. D., Blandino, G., Avantaggiati, M. L., & Chung, F.-L.
Affiliations
  • Georgetown University (US)
  • National Institutes of Health (US)
  • Instituto Nazionale Tumori Regina Elena (IT)
Corresponding author
  • Aggarwal, M
  • Chung, F-L
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2016-06-03
Volume
23
Issue
10
Pages
1615-1627
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2016.48
PMC
PMC5041190
OpenAlex
W2409136177
Cited by
101
References
3
Citations by year
2026: 3 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 19 · 2017: 8 · 2016: 4
FWCI
7.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • University of Pittsburgh
  • Georgetown University (CA51008)
  • National Institutes of Health (CA51008, CA100853)
  • National Cancer Institute (P30 CA-51008, CA-51008, CA100853, R01CA100853, R01CA193698, P30CA051008)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
phenethyl isothiocyanate, mutant p53 reactivation, cruciferous vegetables, apoptosis, cell cycle arrest, proteasomal degradation, autophagy, redox state, tumor growth inhibition, xenograft mouse model, cancer prevention
MeSH terms
Autophagy, Cell Cycle, Diet, Histones, Humans, Mutation, Neoplasms, Oxidation-Reduction, Protein Conformation, Zinc, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Isothiocyanates, Xenograft Model Antitumor Assays, Cell Line, Tumor, Proteasome Endopeptidase Complex, Cell Proliferation, Mutant Proteins, Proteolysis, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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