Authors:	Siemer, Svenja Fauth, Thorsten Scholz, Paul Al-Zamel, Yara Khamis, Aya Gül, Désirée Freudelsperger, Laura Wollenberg, Barbara Becker, Sven Stauber, Roland H. Hagemann, Jan
Title:	Profiling cisplatin resistance in head and neck cancer : a critical role of the VRAC ion channel for chemoresistance
Online publication date:	14-Jan-2022
Year of first publication:	2021
Language:	english
Abstract:	Treatment 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 medicine
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6697
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Cancers 13 19
Pages or article number:	4831
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2021
ISSN:	2072-6694
Publisher URL:	https://doi.org/10.3390/cancers13194831
Publisher DOI:	10.3390/cancers13194831
Appears in collections:	JGU-Publikationen