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The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer
SIMPLE SUMMARY: Treatment success of head and neck squamous cell carcinoma cancers (HNSCCs) is often hindered by cisplatin resistance. Vitamin D and its receptor (VDR) have been suggested to influence tumor pathobiology and therapy response. We found that VitD/analogs in combination with platinum-ba...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600548/ https://www.ncbi.nlm.nih.gov/pubmed/36291915 http://dx.doi.org/10.3390/cancers14205131 |
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author | Khamis, Aya Gül, Désirée Wandrey, Madita Lu, Qiang Knauer, Shirley K. Reinhardt, Christoph Strieth, Sebastian Hagemann, Jan Stauber, Roland H. |
author_facet | Khamis, Aya Gül, Désirée Wandrey, Madita Lu, Qiang Knauer, Shirley K. Reinhardt, Christoph Strieth, Sebastian Hagemann, Jan Stauber, Roland H. |
author_sort | Khamis, Aya |
collection | PubMed |
description | SIMPLE SUMMARY: Treatment success of head and neck squamous cell carcinoma cancers (HNSCCs) is often hindered by cisplatin resistance. Vitamin D and its receptor (VDR) have been suggested to influence tumor pathobiology and therapy response. We found that VitD/analogs in combination with platinum-based drugs may help to fight therapy resistances in HNSCC. VitD/cisplatin combinations induced E-cadherin upregulation and killed cancer cells by increasing the expression of the pro-apoptotic protein BIM. By identifying the VDR/VitD/BIM axis, we here provide a molecular rationale for the anti-cancer activity of VitD/analogs in combination therapies, which should be further exploited in the clinics. 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. |
format | Online Article Text |
id | pubmed-9600548 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96005482022-10-27 The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer Khamis, Aya Gül, Désirée Wandrey, Madita Lu, Qiang Knauer, Shirley K. Reinhardt, Christoph Strieth, Sebastian Hagemann, Jan Stauber, Roland H. Cancers (Basel) Article SIMPLE SUMMARY: Treatment success of head and neck squamous cell carcinoma cancers (HNSCCs) is often hindered by cisplatin resistance. Vitamin D and its receptor (VDR) have been suggested to influence tumor pathobiology and therapy response. We found that VitD/analogs in combination with platinum-based drugs may help to fight therapy resistances in HNSCC. VitD/cisplatin combinations induced E-cadherin upregulation and killed cancer cells by increasing the expression of the pro-apoptotic protein BIM. By identifying the VDR/VitD/BIM axis, we here provide a molecular rationale for the anti-cancer activity of VitD/analogs in combination therapies, which should be further exploited in the clinics. 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. MDPI 2022-10-19 /pmc/articles/PMC9600548/ /pubmed/36291915 http://dx.doi.org/10.3390/cancers14205131 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Khamis, Aya Gül, Désirée Wandrey, Madita Lu, Qiang Knauer, Shirley K. Reinhardt, Christoph Strieth, Sebastian Hagemann, Jan Stauber, Roland H. The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title | The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title_full | The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title_fullStr | The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title_full_unstemmed | The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title_short | The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer |
title_sort | vitamin d receptor–bim axis overcomes cisplatin resistance in head and neck cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600548/ https://www.ncbi.nlm.nih.gov/pubmed/36291915 http://dx.doi.org/10.3390/cancers14205131 |
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