Gutenberg Open Science: The vitamin D receptor–BIM axis overcomes cisplatin resistance in head and neck cancer

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8640

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DC Field	Value	Language
dc.contributor.author	Khamis, Aya	-
dc.contributor.author	Gül, Désirée	-
dc.contributor.author	Wandrey, Madita	-
dc.contributor.author	Lu, Qiang	-
dc.contributor.author	Knauer, Shirley K.	-
dc.contributor.author	Reinhardt, Christoph	-
dc.contributor.author	Strieth, Sebastian	-
dc.contributor.author	Hagemann, Jan	-
dc.contributor.author	Stauber, Roland H.	-
dc.date.accessioned	2023-01-25T11:23:16Z	-
dc.date.available	2023-01-25T11:23:16Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8656	-
dc.description.abstract	Treatment success of head and neck squamous cell carcinoma (HNSCC) is often hindered by cisplatin resistance. As inherent and acquired therapy resistance counteracts improvement in long-term survival, novel multi-targeting strategies triggering cancer cell apoptosis are urgently required. Here, we identify the vitamin D receptor (VDR) as being significantly overexpressed in tumors of HNSCC patients (n = 604; p = 0.0059), correlating with tumor differentiation (p = 0.0002), HPV status (p = 0.00026), and perineural invasion (p = 0.0087). The VDR, a member of the nuclear receptor superfamily, is activated by its ligand vitamin D (VitD) and analogs, triggering multiple cellular responses. As we found that the VDR was also upregulated in our cisplatin-resistant HNSCC models, we investigated its effect on overcoming cisplatin resistance. We discovered that VitD/cisplatin combinations synergistically killed even cisplatin-resistant cells at clinically achievable levels. Similar results were obtained for the clinically used VitD analog Maxacalcitol. Moreover, VitD/cisplatin combinations inhibited tumor cell migration by E-cadherin upregulation. Signaling pathway analyses revealed that VitD co-treatments triggered cancer cell death by increasing the expression of the pro-apoptotic BCL-2 family protein BIM. BIM’s pro-apoptotic activity in HNSCC cells was confirmed by ectopic overexpression studies. Importantly, BIM expression is positively associated with HNSCC patients’ (n = 539) prognosis, as high expression correlated with improved survival (p = 0.0111), improved therapy response (p = 0.0026), and remission (p = 0.004). Collectively, by identifying, for the first time, the VDR/BIM axis, we here provide a molecular rationale for the reported anti-cancer activity of VitD/analogs in combination therapies. Our data also suggest its exploitation as a potential strategy to overcome cisplatin resistance in HNSCC and other malignancies by inducing additional pro-apoptotic pathways.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	The vitamin D receptor–BIM axis overcomes cisplatin resistance in head and neck cancer	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8640	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cancers	de
jgu.journal.volume	14	de
jgu.journal.issue	20	de
jgu.pages.alternative	5131	de
jgu.publisher.year	2022	-
jgu.publisher.name	MDPI	de
jgu.publisher.place	Basel	de
jgu.publisher.issn	2072-6694	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3390/cancers14205131	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Lebenswissenschaften	de
Appears in collections:	DFG-491381577-G

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