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Article

Identification of Novel Rare ABCC1 Transporter Mutations in Tumor Biopsies of Cancer Patients

1
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128 Mainz, Germany
2
Third Department of Medicine (Hematology, Oncology, and Pneumology), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
3
Clinic for Gynecology and Obstetrics, 76131 Karlsruhe, Germany
4
Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-030 Porto, Portugal
5
Heidelberg School of Chinese Medicine, 69126 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 299; https://doi.org/10.3390/cells9020299
Received: 30 December 2019 / Revised: 22 January 2020 / Accepted: 23 January 2020 / Published: 26 January 2020
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
The efficiency of chemotherapy drugs can be affected by ATP-binding cassette (ABC) transporter expression or by their mutation status. Multidrug resistance is linked with ABC transporter overexpression. In the present study, we performed rare mutation analyses for 12 ABC transporters related to drug resistance (ABCA2, -A3, -B1, -B2, -B5, -C1, -C2, -C3, -C4, -C5, -C6, -G2) in a dataset of 18 cancer patients. We focused on rare mutations resembling tumor heterogeneity of ABC transporters in small tumor subpopulations. Novel rare mutations were found in ABCC1, but not in the other ABC transporters investigated. Diverse ABCC1 mutations were found, including nonsense mutations causing premature stop codons, and compared with the wild-type protein in terms of their protein structure. Nonsense mutations lead to truncated protein structures. Molecular docking and heat map analyses of ABCC1/MRP1 pointed out that Lys498* appeared in a separate cluster branch due to the large deletion, leading to a massive disruption in the protein conformation. The resulting proteins, which are nonfunctional due to nonsense mutations in tumors, offer a promising chemotherapy strategy since tumors with nonsense mutations may be more sensitive to anticancer drugs than wild-type ABCC1-expressing tumors. This could provide a novel tumor-specific toxicity strategy and a way to overcome drug resistance. View Full-Text
Keywords: ABC transporters; cancer; multidrug resistance ABC transporters; cancer; multidrug resistance
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MDPI and ACS Style

Kadioglu, O.; Saeed, M.; Munder, M.; Spuller, A.; Greten, H.J.; Efferth, T. Identification of Novel Rare ABCC1 Transporter Mutations in Tumor Biopsies of Cancer Patients. Cells 2020, 9, 299. https://doi.org/10.3390/cells9020299

AMA Style

Kadioglu O, Saeed M, Munder M, Spuller A, Greten HJ, Efferth T. Identification of Novel Rare ABCC1 Transporter Mutations in Tumor Biopsies of Cancer Patients. Cells. 2020; 9(2):299. https://doi.org/10.3390/cells9020299

Chicago/Turabian Style

Kadioglu, Onat, Mohamed Saeed, Markus Munder, Andreas Spuller, Henry J. Greten, and Thomas Efferth. 2020. "Identification of Novel Rare ABCC1 Transporter Mutations in Tumor Biopsies of Cancer Patients" Cells 9, no. 2: 299. https://doi.org/10.3390/cells9020299

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