Backgroundp53 is the most frequently mutated tumor-suppressor gene in human cancers. It has been reported that mutations in p53 result not only in the loss of its ability as a tumor suppressor, but also in the gain of novel cancer-related functions that contribute to oncogenesis. The present study evaluated the potential of silencing of mutant p53 by small interfering RNA in the treatment of bladder cancer cells in vitro.MethodsWe used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability and flow cytometry to detect cell cycle alterations and apoptosis. The related molecular mechanisms were assessed by western blotting. We also used the MTT assay and flow cytometry to investigate if silencing of mutant p53 by knockdown with small interfering (si)RNA would change the sensitivity to cisplatin treatment.ResultsUsing 5637 and T24 human bladder cancer cell lines characterized by mutations in p53, we found that silencing of the mutant p53 by RNA interference induced evident inhibition of cell proliferation and viability, which was related to the induction of G2 phase cell cycle arrest and apoptosis. Moreover, our study also showed that the p53-targeting siRNA cooperated with cisplatin in the inhibition of bladder cancer cells.ConclusionsThese findings suggest that RNA interference targeting mutant p53 may be a promising therapeutic strategy for the treatment of bladder cancer.
The importance of upregulated Wnt signaling in colorectal
cancers
led to efforts to develop inhibitors that target β-catenin in
this pathway. We now report that several “Wnt inhibitors”
that allegedly target β-catenin actually function as mitochondrial
proton uncouplers that independently activate AMPK and concomitantly
inhibit Wnt signaling. As expected for a process in which mitochondrial
uncoupling diminishes ATP production, a mitochondrial proton uncoupler,
FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and
inhibited Wnt signaling. Also consistent with these findings, a well-known
“Wnt inhibitor”, FH535, functioned as a proton uncoupler,
and in support of this finding, the N-methylated
analog, 2,5-dichloro-N-methyl-N-(2-methyl-4-nitrophenyl)benzenesulfonamide
(FH535-M), was inactive as an uncoupler and Wnt inhibitor. Apart from
suggesting an opportunity to develop dual Wnt inhibitors and AMPK
activators, these findings provide a cautionary tale that claims for
Wnt inhibition alone require scrutiny as possible mitochondrial proton
uncouplers or inhibitors of the electron transport chain.
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