Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs
| Autor: | Mark Merchant, Nisebita Sahu, Richard Bourgon, Marie Classon, Darlene Dela Cruz, Jean-Philippe Stephan, Jeff Settleman, Benjamin Haley |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Kinase C-alpha Science Cell Phospholipase C beta Down-Regulation General Physics and Astronomy Antineoplastic Agents Drug resistance Pharmacology Biology Article General Biochemistry Genetics and Molecular Biology law.invention 03 medical and health sciences Downregulation and upregulation Drug tolerance law Cell Line Tumor microRNA medicine Humans Multidisciplinary Base Sequence Cancer General Chemistry medicine.disease MicroRNAs Phospholipases A2 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Cell culture Cancer research Suppressor Peroxiredoxin VI |
| Zdroj: | Nature Communications, Vol 7, Iss 1, Pp 1-10 (2016) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters that is dynamically maintained within a wide variety of tumour cell populations. Here we explore a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs reveals miR-371-3p as a potent suppressor of drug tolerance. We identify PRDX6 (peroxiredoxin 6) as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCα activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of peroxiredoxin 6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance. Acquired resistance significantly limits the efficacy of cancer drug therapies. Here, the authors identify miR-371-3p as a suppressor of drug tolerance in cancer cell lines by its target gene PRDX6, which in turn regulates PLA2/PKCα signalling and ROS levels. |
| Databáze: | OpenAIRE |
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