Inhibition of NAD(P)H_quinone oxidoreductase

Inhibition of NAD(P)H_quinone oxidoreductase

NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates the stability
of the tumor suppressor WT p53. NQO1 binds and stabilizes WT
p53, whereas NQO1 inhibitors including dicoumarol and various
other coumarins and flavones induce ubiquitin-independent proteasomal
p53 degradation and thus inhibit p53-induced apoptosis.
Here, we show that curcumin, a natural phenolic compound found
in the spice turmeric, induced ubiquitin-independent degradation
of WT p53 and inhibited p53-induced apoptosis in normal thymocytes
and myeloid leukemic cells. Like dicoumarol, curcumin inhibited
the activity of recombinant NQO1 in vitro, inhibited the
activity of endogenous cellular NQO1 in vivo, and dissociated
NQO1-WT p53 complexes. Neither dicoumarol nor curcumin dissociated
the complexes of NQO1 and the human cancer hot-spot p53
R273H mutant and therefore did not induce degradation of this
mutant. NQO1 knockdown by small-interfering RNA induced degradation
of both WT p53 and the p53 R273H mutant. The results
indicate that curcumin induces p53 degradation and inhibits p53-
induced apoptosis by an NQO1-dependent pathway…

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