Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity
| العنوان: | Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity |
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| المؤلفون: | Jitender Monga, Indra Adrianto, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Joshi J. Alumkal, Himisha Beltran, Amina Zoubeidi, Jagadananda Ghosh |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | TRIB2, Tribbles 2, Male, NE, neuroendocrine, Accelerated Communication, transdifferentiation, Cell Plasticity, pseudokinase, lineage plasticity, CHGA, Chromogranin-A, Biochemistry, Cell Line, Tumor, Nitriles, Phenylthiohydantoin, TMA, tissue microarray, neuroendocrine, Humans, Cell Lineage, TRIB2-OE, TRIB2-overexpressing, Molecular Biology, BRN2, Brain-2, TRIB2, enzalutamide resistance, Prostatic Neoplasms, Cell Biology, AFA, Afatinib, SOX2, SRY-box 2, prostate cancer, CK-8, cytokeratin 8, Drug Resistance, Neoplasm, Receptors, Androgen, SYP, Synaptophysin, Benzamides, Calcium-Calmodulin-Dependent Protein Kinases, AR, androgen receptor, NSE, Enolase-2 |
| الوصف: | Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5a8bb1662a1499b7161cd3cc524395ab http://europepmc.org/articles/PMC8800106 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....5a8bb1662a1499b7161cd3cc524395ab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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