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Abstract
The p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity. A cell-based screening method with a p53-responsive luciferase-reporter assay system revealed that an ethanol extract of Oroxylum indicum bark increased p53 transcriptional activity. Chrysin was isolated and identified as the active ingredient in the O. indicum bark extract. A treatment with chrysin increased p53 protein expression and the p53-mediated expression of downstream target genes, and decreased cell viability in MCF7 cells, but not in p53-knockdown MCF7 cells. We also found that chrysin activated the ATM-Chk2 pathway in the absence of DNA damage. Hence, the inactivation of the ATM-Chk2 pathway suppressed p53 activation induced by chrysin. These results suggest the potential of chrysin as an anti-cancer drug through the activation of p53 without DNA damage.
Highlights
The p53 protein, the guardian of the genome, plays an important role in regulating cell proliferation during various stimuli, including genotoxic stress and oncogenic activation [1,2,3].It functions as a transcription factor that activates the various genes responsible for cell cycle arrest, senescence, or apoptosis, thereby preventing tumor cell progression [3,4]
We found several extracts that induce p53 activation, many of which involved DNA damage
Since Chk2 serves as an ATM downstream effector to mediate the activation of p53, we investigated whether Chk2 is responsible for the activation of p53 by chrysin
Summary
The p53 protein, the guardian of the genome, plays an important role in regulating cell proliferation during various stimuli, including genotoxic stress and oncogenic activation [1,2,3].It functions as a transcription factor that activates the various genes responsible for cell cycle arrest, senescence, or apoptosis, thereby preventing tumor cell progression [3,4]. The incidence of TP53 mutations differs significantly between cancer. Molecules 2018, 23, 1394 types, ranging from nearly universal mutations in serous ovarian cancer to rarely occurring in thyroid cancer [5]. In a large proportion of cancers that retain wild-type (WT) p53, the function of p53 may be compromised by several mechanisms; this offers an attractive strategy for cancer therapy based on p53 activation [6,7]. Small-molecule drugs that inhibit the activity of Mdm, the ubiquitin ligase regulating p53 protein levels, have been developed and entered preclinical trials [8]. The development of therapeutic interventions to overcome the inactivation of p53 may lead to the prevention and treatment of cancer
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