Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung can

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The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms,and its reactivation represents an attractive therapeutic strategy for cancers.Here,we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer(NSCLC)cells which express wild type(wt)p53,in contract to its much weaker cytotoxicity on cells with mutant p53.RYL-687 upregulated p53 in cells with wt but not mutant p53,and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound.RYL-687 induced production of reactive oxygen species(ROS)and upregulation of Nrf2,leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1(NQO1)that can protect p53 by inhibiting its degradation by 20S proteasome.RYL-687 bound NQO1,facilitating the physical interaction between NQO1 and p53.NQO1 was required for RYL-687-induced p53 accumulation,because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine,drastically suppressed RYL-687-induced p53 upregulation.Moreover,a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model.These data indicate that targeting NQO1 is a rational strategy to reactivate p53,and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.
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