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Phenylhexyl isothiocyanate suppresses cell proliferation and promotes apoptosis via repairing mutant P53 in human myeloid leukemia M2 cells.

ABSTRACT: The aim of the present study was to investigate the specific effect and possible mechanisms of phenylhexyl isothiocyanate (PHI) on cell proliferation and apoptosis in acute myeloid leukemia M2 cell lines. Cell proliferation in several hematological tumor cells lines following PHI treatment was evaluated in vitro using a Cell Counting Kit-8. The apoptosis and cell cycle of Kasumi-1 and SKNO-1 cells (human M2 cell lines) following exposure to PHI were examined using flow cytometry. A colony-formation assay was used to identify the inhibitory effect of PHI on Kasumi-1 cells in vitro. Furthermore, Kasumi-1 ×enograft tumor models were established. The antitumor effect of PHI was observed in vivo by measuring the size of the resulting xenograft tumors. The apoptosis of the xenograft tumor cells was measured using a TUNEL assay. Finally, protein expression levels were assessed by western blotting. PHI inhibited cell growth in 16 hematological tumor cell lines, with Kasumi-1 and SKNO-1 cells being the most sensitive. In vitro treatment induced apoptosis and inhibited cell cycle arrest at the G₀/G₁ phase in a dose- and time-dependent manner. PHI also inhibited growth and induced apoptosis in vivo. The compound increased the expression of caspases 3, 9 and 8, Fas and poly (ADP-ribose) polymerase. Furthermore, PHI enhanced the protein expression of p53, Bax and p21 in a dose-dependent manner. In conclusion, PHI had a specific and notable inhibitory effect on Kasumi-1 and SKNO-1 M2 cell lines in vivo and in vitro. Treatment inhibited cell cycle arrest at the G₀/G₁ phase, and induced apoptosis through the mitochondrial and Fas death receptor pathways. PHI restored the activity of mutated P53 and reactivated the P53 pathway, highlighting it as a potential target drug for mutated P53.

SUBMITTER: Zou Y

PROVIDER: S-EPMC6676407 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Phenylhexyl isothiocyanate suppresses cell proliferation and promotes apoptosis via repairing mutant <i>P53</i> in human myeloid leukemia M2 cells.

Zou Yong Y Huang Yiqun Y Ma Xudong X

Oncology letters 20190716 3

The aim of the present study was to investigate the specific effect and possible mechanisms of phenylhexyl isothiocyanate (PHI) on cell proliferation and apoptosis in acute myeloid leukemia M2 cell lines. Cell proliferation in several hematological tumor cells lines following PHI treatment was evaluated <i>in vitro</i> using a Cell Counting Kit-8. The apoptosis and cell cycle of Kasumi-1 and SKNO-1 cells (human M2 cell lines) following exposure to PHI were examined using flow cytometry. A colony ...[more]

PMID: 31452815

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Project description: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.

Dataset Information

Phenylhexyl isothiocyanate suppresses cell proliferation and promotes apoptosis via repairing mutant P53 in human myeloid leukemia M2 cells.

Publications

Phenylhexyl isothiocyanate suppresses cell proliferation and promotes apoptosis via repairing mutant <i>P53</i> in human myeloid leukemia M2 cells.

Similar Datasets

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