Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation
| Autor: | Clarence E Chu, Vivek K. Arora, Andrew E. Schriefer, Angela M Halstead, Gregory R. Bowman, Chiraag D Kapadia, Jennifer Bolzenius, Lukas D. Wartman |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Peroxisome proliferator-activated receptor gamma QH301-705.5 Science medicine.medical_treatment RXRA Mutant medicine.disease_cause General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine KDM6A TP53 Biology (General) Receptor Mutation Bladder cancer General Immunology and Microbiology business.industry General Neuroscience Cancer General Medicine Immunotherapy medicine.disease 3. Good health PPARD 030104 developmental biology Cancer cell PPARG Cancer research bladder cancer Medicine lipids (amino acids peptides and proteins) business |
| Zdroj: | eLife, Vol 6 (2017) |
| ISSN: | 2050-084X |
| Popis: | Bladder cancer is the sixth most common type of cancer in the United States. At the moment, treatment options for advanced bladder cancer are limited to chemotherapy and immunotherapy, both of which benefit only some patients. Many other types of cancer can be treated with drugs that are specific to genetic mutations found in those cancer cells, often making the treatments more efficient with fewer side effects. Between 5–8% of people with bladder cancer have a mutation in the gene that produces a protein called RXRA. This protein partners with itself or with other proteins to control gene activity. However, it was not clear what mutant RXRA proteins do in bladder cancer cells. Halstead et al. studied the RXRA mutation in human bladder cancer cells and “mini-bladders” grown in the laboratory from mouse bladder cells. Biochemical experiments showed that the mutant RXRA protein causes abnormally high activity in one group of its partner proteins, called peroxisome proliferator-activated receptors (PPARs). The PPARs, in turn, switch on genes that help cancer cells to grow and multiply. Computational simulations of the mutant RXRA binding to PPARs revealed, at a molecular level, how this activation occurs. Lastly, Halstead et al. used chemicals that block the activity of PPARs to stop the growth of cells in the mouse mini-bladders that contained the RXRA mutation. These findings suggest that bladder cancer patients with the RXRA mutation may benefit from therapies that inhibit PPARs. Such therapies could also benefit the approximately 15–20% of people with bladder cancer who do not have the RXRA mutation but who do have over-active PPARs. Although there are chemicals that block the activity of PPARs, more research is needed to refine them before they can be used to treat cancer. |
| Databáze: | OpenAIRE |
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