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The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

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.

SUBMITTER: Khamis A

PROVIDER: S-EPMC9600548 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

Khamis Aya A Gül Désirée D Wandrey Madita M Lu Qiang Q Knauer Shirley K SK Reinhardt Christoph C Strieth Sebastian S Hagemann Jan J Stauber Roland H RH

Cancers 20221019 20

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; <i>p</i> = 0.0059), correlating with tumor differentiation (<i>p</i> = 0.0002), HPV stat ...[more]

PMID: 36291915

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Project description:BackgroundCisplatin resistance is one of the major contributors to the poor survival rate among head and neck cancer (HNC) patients. Focusing on the protein-protein interaction rather than a single protein could provide a better understanding of drug resistance. Thus, this study aimed to identify hub genes in a complex network of cisplatin resistance associated genes in HNC chemotherapy via a series of bioinformatic tools.MethodsThe genes involved in cisplatin resistance were retrieved from the NCBI gene database using "head and neck cancer" and "cisplatin resistance" as key words. The human genes retrieved were analyzed for their interactions and enriched using the STRING database. The interaction between KEGG pathways and genes was visualized in Cytoscape 3.7.2. Further, the hub gene was identified using the Cytohubba plugin of Cytoscape and validated using UALCAN and Human Protein Atlas database. Validated genes were investigated for the drug-gene interaction using the DGIbd database.ResultsOut of 137 genes obtained using key words, 133 were associated with cisplatin resistance in the human species. A total of 150 KEGG pathways, 82 cellular components, 123 molecular functions, and 1752 biological processes were modulated on enrichment analysis. Out of 37 hub genes, CCND1, AXL, CDKN2A, TERT, and EXH2 genes were found to have significant (p < 0.05) mRNA expression and effect on overall survival whereas protein expression was found to be positive for all the significant genes except TERT. Thus, they can be targeted with palbociclib, methotrexate, bortezomib and fluorouracil, sorafenib, dasatinib, carboplatin, paclitaxel, gemcitabine, imatinib, doxorubicin, and vorinostat.ConclusionAs the pathogenesis of head and neck cancer is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance which might uplift overall survival among HNC patients.

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The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

Publications

The Vitamin D Receptor-BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer.

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