Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-6697
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dc.contributor.authorSiemer, Svenja-
dc.contributor.authorFauth, Thorsten-
dc.contributor.authorScholz, Paul-
dc.contributor.authorAl-Zamel, Yara-
dc.contributor.authorKhamis, Aya-
dc.contributor.authorGül, Désirée-
dc.contributor.authorFreudelsperger, Laura-
dc.contributor.authorWollenberg, Barbara-
dc.contributor.authorBecker, Sven-
dc.contributor.authorStauber, Roland H.-
dc.contributor.authorHagemann, Jan-
dc.date.accessioned2022-01-14T11:08:18Z-
dc.date.available2022-01-14T11:08:18Z-
dc.date.issued2021-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/6707-
dc.description.abstractTreatment success of head and neck cancers (HNSCC) is often hindered by tumor relapses due to therapy resistances. This study aimed at profiling cisplatin resistance mechanisms and identifying biomarkers potentially suitable as drug targets and for patient stratification. Bioinformatic analyses of suggested resistance factors in a cohort of 565 HNSCC patients identified the VRAC ion channel as a clinically relevant indicator for recurrent diseases following radiochemotherapy (p = 0.042). Other drug import/export transporters, such as CTR1, OCT1, or MRP1, were found to be less relevant. To experimentally verify VRAC’s critical role for cisplatin resistance, we used CRISPR/Cas9 knockout resulting in cisplatin-resistant HNSCC cells, which could be resensitized by VRAC expression. Next-generation sequencing further underlined VRAC’s importance and identified VRAC-regulated signaling networks, potentially also contributing to cisplatin resistance. CTR1, OCT1, or MRP1 did not contribute to increased cisplatin resistance. In addition to two-dimensional HNSCC models, three-dimensional tumor spheroid cultures confirmed VRAC’s unique role for cisplatin sensitivity. Here, resistance correlated with DNA damage and downstream apoptosis. The cisplatin specificity of the identified VRAC pathway was verified by testing paclitaxel and doxorubicin. Our results were independently confirmed in naturally occurring, cisplatin-resistant HNSCC cancer cell models. Collectively, we here demonstrate VRAC’s role for cisplatin resistance in HNSCC and its relevance as a potential drug target and/or prognostic biomarker for chemotherapy resistance. Keywords: chemotherapy resistance HNSCC tumor therapy drug transporter personalized medicineen_GB
dc.description.sponsorshipOpen Access-Publizieren Universität Mainz / Universitätsmedizin Mainzde
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleProfiling cisplatin resistance in head and neck cancer : a critical role of the VRAC ion channel for chemoresistanceen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-6697-
jgu.type.contenttypeScientific articlede
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titleCancersde
jgu.journal.volume13de
jgu.journal.issue19de
jgu.pages.alternative4831de
jgu.publisher.year2021-
jgu.publisher.nameMDPIde
jgu.publisher.placeBaselde
jgu.publisher.urihttps://doi.org/10.3390/cancers13194831de
jgu.publisher.issn2072-6694de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.3390/cancers13194831
jgu.organisation.rorhttps://ror.org/023b0x485
Appears in collections:JGU-Publikationen

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