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p53 mutant-type in human prostate cancer cells determines the sensitivity to phenethyl isothiocyanate induced growth inhibition.
- Source :
-
Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2019 Jul 15; Vol. 38 (1), pp. 307. Date of Electronic Publication: 2019 Jul 15. - Publication Year :
- 2019
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Abstract
- Background: We reported previously that phenethyl isothiocyanate (PEITC), a dietary compound, can reactivate p53 <superscript>R175H</superscript> mutant in vitro and in SK-BR-3 (p53 <superscript>R175H</superscript> ) breast xenograft model resulting in tumor inhibition. Because of the diversity of human cancers with p53 mutations, these findings raise important questions whether this mechanism operates in different cancer types with same or different p53 mutations. In this study, we investigated whether PEITC recuses mutant p53 in prostate cancer cells harboring different types of p53 mutants, structural and contact, in vitro and in vivo.<br />Methods: Cell proliferation, cell apoptosis and cell cycle arrest assays were performed to examine the effects of PEITC on prostate cancer cell lines with p53 mutation(s), wild-type p53, p53 null or normal prostate cells in vitro. Western blot analysis was used to monitor the expression levels of p53 protein, activation of ATM and upregulation of canonical p53 targets. Immunoprecipitation, subcellular protein fraction and qRT-PCR was performed to determine change in conformation and restoration of transactivation functions/ inhibition of gain-of-function (GOF) activities to p53 mutant(s). Mice xenograft models were established to evaluate the antitumor efficacy of PEITC and PEITC-induced reactivation of p53 mutant(s) in vivo. Immunohistochemistry of xenograft tumor tissues was performed to determine effects of PEITC on expression of Ki67 and mutant p53 in vivo.<br />Results: We demonstrated that PEITC inhibits the growth of prostate cancer cells with different "hotspot" p53 mutations (structural and contact), however, preferentially towards structural mutants. PEITC inhibits proliferation and induces apoptosis by rescuing mutant p53 in p53 <superscript>R248W</superscript> contact (VCaP) and p53 <superscript>R175H</superscript> structural (LAPC-4) mutant cells with differential potency. We further showed that PEITC inhibits the growth of DU145 cells that co-express p53 <superscript>P223L</superscript> (structural) and p53 <superscript>V274F</superscript> (contact) mutants by targeting p53 <superscript>P223L</superscript> mutant selectively, but not p53 <superscript>V274F</superscript> . The mutant p53 restored by PEITC induces apoptosis in DU145 cells by activating canonical p53 targets, delaying cells in G1 phase and phosphorylating ATM. Importantly, PEITC reactivated p53 <superscript>R175H</superscript> and p53 <superscript>P223L/V274F</superscript> mutants in LAPC-4 and DU145 prostate xenograft models, respectively, resulting in significant tumor inhibition.<br />Conclusion: Our studies provide the first evidence that PEITC's anti-cancer activity is cancer cell type-independent, but p53 mutant-type dependent.
- Subjects :
- Animals
Anticarcinogenic Agents pharmacology
Ataxia Telangiectasia Mutated Proteins metabolism
Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Humans
Isothiocyanates pharmacology
Male
Mice
Mutation
Phosphorylation
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Tumor Suppressor Protein p53 metabolism
Xenograft Model Antitumor Assays
Anticarcinogenic Agents administration & dosage
Isothiocyanates administration & dosage
Prostatic Neoplasms drug therapy
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1756-9966
- Volume :
- 38
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of experimental & clinical cancer research : CR
- Publication Type :
- Academic Journal
- Accession number :
- 31307507
- Full Text :
- https://doi.org/10.1186/s13046-019-1267-z