Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification

SIMPLE SUMMARY: The resistance formation of cancer cells to chemotherapeutic drugs is one of the main reasons for the failure of cancer therapy. In order to combat drug resistance and improve the efficacy of chemotherapeutic drugs, we studied the role of the multifaceted hsa-miR-200c in different tumor types. We identified hsa-miR-200c as an important player regulating phase II detoxification and thus sensitizing cells to chemotherapeutics and reverse drug resistance. In a xenograft mouse experiment, the mutual expression of hsa-miR-200c and chemotherapeutic treatment led to a regression of tumor size and eventually to the survival of 60% of the mice. These findings highlight hsa-miR-200c both as a potential prognostic marker for chemotherapy and as a novel therapeutic option in cancer therapy. ABSTRACT: 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.