Pyrogallol promotes growth arrest by activating the p53-mediated up-regulation of p21 and p62/SQSTM1-dependent degradation of -catenin in nonsmall cell lung cancer cells
Environmental toxicology(2024)
Abstract
Pyrogallol (1,2,3-trihydroxybenzene), a polyphenolic natural compound, has attracted considerable attention with regard to its potential anticancer activity. However, further study is needed to elucidate the underlying mechanism related to the antiNSCLC activity of pyrogallol and provide a comprehensive theoretical basis for better clinical utilization of pyrogallol. Our current study aims to investigate the effects and potential underlying mechanisms of pyrogallol on the inhibition of NSCLC growth. Our results showed that pyrogallol treatment induced cell cycle arrest at the G2/M phase and apoptosis in two different NSCLC cell lines. Mechanistically, we found that the induction of cell cycle arrest in NSCLC cells at the G2/M phase by pyrogallol was due to the upregulation of p21 in a p53-dependent manner. And blockade of p53 and p21 effectively abolished the cell cycle arrest at the G2/M phase. Meanwhile, p53 inhibition has been found to abrogate the pyrogallol-induced apoptosis of the two NSCLC cells. Moreover, we revealed that the inhibitory effects of pyrogallol on beta-catenin signaling resulted from autophagy initiation depending on p53 activation, accompanied by an increase in p62/SQSTM1 expression, thus p62 subsequently interacting with ubiquitinated beta-catenin and facilitating autophagic destruction of beta-catenin. Furthermore, in vivo experiments demonstrated that pyrogallol exerted growth inhibition on NSCLC with low toxicity through the same molecular mechanism as observed in vitro. Our findings could contribute to the understanding of the mechanism by which pyrogallol negatively regulates NSCLC growth, which could be effective in treating NSCLC.
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Key words
autophagy,nonsmall cell lung cancer cells,p53,pyrogallol,ubiquitination
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