A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.Show MeSH
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Mentions: To further characterize the effect of INZ on p53 cellular functions, we performed a set of time course experiments using the same aforementioned approaches with 2 µM INZ, as this concentration was sufficient to significantly induce p53 level and activity (Fig 1D). We found that INZ induced p53 level in a time-dependent manner as early as 6 h post-treatment in both p53-containing H460 and HCT116 cells (Fig 2A). Correspondingly, three of p53 targets, MDM2, p21 and Puma, were also induced in a time-dependent manner in p53-containing H460 and HCT116, but not in p53- H1299 and HCT116, cells (Fig 2A). Interestingly, Puma was induced earlier (3–6 h) and cleaved PARP was detected later on (∼12 h; Fig 2A). Apparently, cleaved PARP was p53-dependent as it was not detected in p53- cells (Fig 2A). The induction of p53 targets was clearly at the transcriptional level as p21 mRNA and miR34a, but not p53 mRNA and miR24, were highly induced in H460 cells (Fig 2B and C).
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.