Altogether, our results demonstrate that RBM10 inhibits cancer cell proliferation and induces apoptosis in part by blocking the MDM2-p53 feedback loop.
There was also significant difference in TG genotype distribution in the MDM2T309G polymorphism between those with and without cancer (OR=1.98, 95% CI=1.98-3.91, x2=4.00, p=0.045).
Therapeutic antagonism of MDM2 by small molecules and peptides in clinical development for treatment of cancer patients was assayed using the MDM2-binding CueO enzyme.
One such small molecule drug Nutlin binds the protein MDM2, which is upregulated in several types of cancer and is a negative regulator of the tumor suppressor protein p53.
Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4.
Dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC.
Targeting MDM2 in 1601-a Gprc5a-ko mouse derived lung tumor cell line-and A549-human lung cancer cells, by MDM2 inhibitor Nutlin-3a or small hairpin RNA (sh-RNA)-restored p53 signaling pathway, reduced cancer stem cell markers, and inhibited tumorigenicity.
This investigation elucidated the mechanism of how MDM2 promotes genome instability and enhances tumorigenesis in the absence of p53, thus providing a theoretical and experimental basis for targeting MDM2 as a cancer therapy.
This discovery suggests potential clinical trials of MDM2 inhibitors in patients with MRT.<i>See related article by Howard and colleagues; Cancer Res 79(9):2404-14</i>.
In this present review, we propose the probable molecular crosstalk involving UCK2 protein and cancer cell death through cell cycle arrest and triggering of apoptosis involving proteins, MDM2 and the subsequent activation of p53.
The efficacy of the proposed methodology is demonstrated via numerical experiments using a p53-MDM2 negative feedback loop Boolean network with stuck-at faults that model molecular events commonly found in cancer.
It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction.
Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16<sup>INK4A</sup> and p14<sup>ARF</sup>, two tumor suppressor genes.
As a result, restoration of p53 function by inhibiting p53-MDM2 protein-protein interaction has been pursued as a compelling strategy for cancer therapy.
Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer.
Amplification and overexpression of MDM2 gene is frequent in glioblastoma and disrupting the MDM2-p53 interaction is a promising strategy to treat the cancer.
Currently, the MDM2 promoter rs937283 A > G variant that is able to alter MDM2 gene expression has been widely studied to explore the association of MDM2 with cancer risk.