Pharmacological and genetic targeting of 5-lipoxygenase interrupts c-Myc oncogenic signaling and kills enzalutamide-resistant prostate cancer cells via apoptosis
| Autor: | Ajay Bharathan, Jagadananda Ghosh, Dhatchayini Subramani, Jitender Monga |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Indoles Cell Survival lcsh:Medicine Antineoplastic Agents Apoptosis Article Metastasis Cell Line Small hairpin RNA Proto-Oncogene Proteins c-myc Prostate cancer chemistry.chemical_compound Cell Line Tumor Nitriles Phenylthiohydantoin medicine Enzalutamide Humans RNA Small Interfering lcsh:Science Cell Proliferation Multidisciplinary Arachidonate 5-Lipoxygenase biology business.industry Cell growth lcsh:R Prostate Fibroblasts medicine.disease Androgen receptor Gene Expression Regulation Neoplastic chemistry 5-Lipoxygenase-Activating Protein Inhibitors Drug Resistance Neoplasm Organ Specificity Arachidonate 5-lipoxygenase Benzamides biology.protein Cancer research Quinolines lcsh:Q business Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2045-2322 |
| Popis: | Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by blocking androgen receptor function. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Though the mechanism behind enzalutamide-resistance is not properly understood, over-activation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancer-specific way. We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells. Transcriptional activity of c-Myc was analyzed by DNA-binding, luciferase-assays, and expression of c-Myc-target genes. We found that 5-Lox regulates c-Myc signaling in enzalutamide-resistant prostate cancer cells and inhibition of 5-Lox by Quiflapon/MK591 or shRNA interrupts oncogenic c-Myc signaling and kills ERPC cells by triggering caspase-mediated apoptosis. Interestingly, MK591 does not affect normal, non-cancer cells in the same experimental conditions. Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors. |
| Databáze: | OpenAIRE |
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