Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification
Acquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR-...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/22/5554 |
| _version_ | 1797465750106013696 |
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| author | Bianca Köhler Sviatlana Dubovik Elisa Hörterer Ulrich Wilk Jan Bernd Stöckl Hande Tekarslan-Sahin Bojan Ljepoja Philipp Paulitschke Thomas Fröhlich Ernst Wagner Andreas Roidl |
| author_facet | Bianca Köhler Sviatlana Dubovik Elisa Hörterer Ulrich Wilk Jan Bernd Stöckl Hande Tekarslan-Sahin Bojan Ljepoja Philipp Paulitschke Thomas Fröhlich Ernst Wagner Andreas Roidl |
| author_sort | Bianca Köhler |
| collection | DOAJ |
| description | Acquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR-200c on drug resistance were elucidated. Upon knockout of hsa-miR-200c in breast carcinoma cells, a proteomic approach identified altered expression of glutathione S-transferases (GSTs) when cells were treated with the chemotherapeutic drug doxorubicin. In different hsa-miR-200c expression systems, such as knockout, inducible sponge and inducible overexpression, the differential expression of all members of the GST family was evaluated. Expression of hsa-miR-200c in cancer cells led to the repression of a multitude of these GSTs and as consequence, enhanced drug-induced tumor cell death which was evaluated for two chemotherapeutic drugs. Additionally, the influence of hsa-miR-200c on the glutathione pathway, which is part of the phase II detoxification mechanism, was investigated. Finally, the long-term effects of hsa-miR-200c on drug efficacy were studied in vitro and in vivo. Upon doxycycline induction of hsa-miR-200c, MDA-MB 231 xenograft mouse models revealed a strongly reduced tumor growth and an enhanced treatment response to doxorubicin. A combined treatment of these tumors with hsa-miR-200c and doxorubicin resulted in complete regression of the tumor in 60% of the animals. These results identify hsa-miR-200c as an important player regulating the cellular phase II detoxification, thus sensitizing cancer cells not expressing this microRNA to chemotherapeutics and reversing drug resistance through suppression of GSTs. |
| first_indexed | 2024-03-09T18:26:57Z |
| format | Article |
| id | doaj.art-fefd982d22e6440aa5c3d898c10c04cc |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T18:26:57Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fefd982d22e6440aa5c3d898c10c04cc2023-11-24T07:53:03ZengMDPI AGCancers2072-66942022-11-011422555410.3390/cancers14225554Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II DetoxificationBianca Köhler0Sviatlana Dubovik1Elisa Hörterer2Ulrich Wilk3Jan Bernd Stöckl4Hande Tekarslan-Sahin5Bojan Ljepoja6Philipp Paulitschke7Thomas Fröhlich8Ernst Wagner9Andreas Roidl10Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyLaboratory of Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPHIO Scientific GmbH, Esswurmstr. 16, D-81371 Munich, GermanyLaboratory of Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, GermanyAcquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR-200c on drug resistance were elucidated. Upon knockout of hsa-miR-200c in breast carcinoma cells, a proteomic approach identified altered expression of glutathione S-transferases (GSTs) when cells were treated with the chemotherapeutic drug doxorubicin. In different hsa-miR-200c expression systems, such as knockout, inducible sponge and inducible overexpression, the differential expression of all members of the GST family was evaluated. Expression of hsa-miR-200c in cancer cells led to the repression of a multitude of these GSTs and as consequence, enhanced drug-induced tumor cell death which was evaluated for two chemotherapeutic drugs. Additionally, the influence of hsa-miR-200c on the glutathione pathway, which is part of the phase II detoxification mechanism, was investigated. Finally, the long-term effects of hsa-miR-200c on drug efficacy were studied in vitro and in vivo. Upon doxycycline induction of hsa-miR-200c, MDA-MB 231 xenograft mouse models revealed a strongly reduced tumor growth and an enhanced treatment response to doxorubicin. A combined treatment of these tumors with hsa-miR-200c and doxorubicin resulted in complete regression of the tumor in 60% of the animals. These results identify hsa-miR-200c as an important player regulating the cellular phase II detoxification, thus sensitizing cancer cells not expressing this microRNA to chemotherapeutics and reversing drug resistance through suppression of GSTs.https://www.mdpi.com/2072-6694/14/22/5554cancerglutathione S-transferasemiR-200cchemotherapyresistance |
| spellingShingle | Bianca Köhler Sviatlana Dubovik Elisa Hörterer Ulrich Wilk Jan Bernd Stöckl Hande Tekarslan-Sahin Bojan Ljepoja Philipp Paulitschke Thomas Fröhlich Ernst Wagner Andreas Roidl Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification Cancers cancer glutathione S-transferase miR-200c chemotherapy resistance |
| title | Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification |
| title_full | Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification |
| title_fullStr | Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification |
| title_full_unstemmed | Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification |
| title_short | Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification |
| title_sort | combating drug resistance by exploiting mirna 200c controlled phase ii detoxification |
| topic | cancer glutathione S-transferase miR-200c chemotherapy resistance |
| url | https://www.mdpi.com/2072-6694/14/22/5554 |
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