CB002, a novel p53 tumor suppressor pathway-restoring small molecule induces tumor cell death through the pro-apoptotic protein NOXA
| Autor: | Liz J. Hernandez-Borrero, Wafik S. El-Deiry, Shengliang Zhang, Amriti R. Lulla, David T. Dicker |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cyclin-Dependent Kinase Inhibitor p21 Programmed cell death Tumor suppressor gene Cell Survival Leupeptins Apoptosis 03 medical and health sciences Cell Line Tumor Humans RNA Small Interfering Molecular Biology Transcription factor Caspase Gene knockdown Aniline Compounds biology Cell Biology G1 Phase Cell Cycle Checkpoints Cell biology Receptors TNF-Related Apoptosis-Inducing Ligand 030104 developmental biology Proteasome Proto-Oncogene Proteins c-bcl-2 Purines Cancer cell biology.protein Mutagenesis Site-Directed RNA Interference Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 Developmental Biology Reports |
| Zdroj: | Cell cycle (Georgetown, Tex.). 17(5) |
| ISSN: | 1551-4005 |
| Popis: | P53 tumor suppressor gene mutations occur in the majority of human cancers and contribute to tumor development, progression and therapy resistance. Direct functional restoration of p53 as a transcription factor has been difficult to achieve in the clinic. We performed a functional screen using a bioluminescence-based transcriptional read-out to identify small molecules that restore the p53 pathway in mutant p53-bearing cancer cells. We identified CB002, as a candidate that restores p53 function in mutant p53-expressing colorectal cancer cells and without toxicity to normal human fibroblasts. Cells exposed to CB002 show increased expression of endogenous p53 target genes NOXA, DR5, and p21 and cell death which occurs by 16 hours, as measured by cleaved caspases or PARP. Stable knockdown of NOXA completely abrogates PARP cleavage and reduces sub-G1 content, implicating NOXA as the key mediator of cell death induction by CB002. Moreover, CB002 decreases the stability of mutant p53 in RXF393 cancer cells and an exogenously expressed R175H p53 mutant in HCT116 p53-null cells. R175H p53 expression was rescued by addition of proteasome inhibitor MG132 to CB002, suggesting a role for ubiquitin-mediated degradation of the mutant protein. In summary, CB002, a p53 pathway-restoring compound that targets mutant p53 for degradation and induces tumor cell death through NOXA, may be further developed as a cancer therapeutic. |
| Databáze: | OpenAIRE |
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