Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck

International Journal of Molecular Sciences · 10 authors, 4 centres

AI SUMMARY

FIDELITY 100%

POPULATIONPatients with head and neck squamous cell carcinomas (HNC) (n=40) and healthy controls (n=40); HNC cell lines (FaDu, HNCUM-02T, Pica, etc.)

INTERVENTIONVitamin D (VitD) treatment, alone or in combination with cisplatin

COMPARISONCisplatin alone; untreated controls; healthy individuals vs. HNC patients

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This study investigated the clinical and preclinical relevance of the vitamin D receptor (VDR)/vitamin D (VitD) axis in head and neck squamous cell carcinomas (HNC). It found that VDR expression and serum VitD levels correlate with tumor differentiation, and that VitD synergistically enhances cisplatin killing of HNC cells in 2D and 3D models, potentially via mTOR/PI3K-Akt pathway inhibition. A key limitation is the small, geographically specific patient cohort (n=40), which may limit generalizability.

Full summary

1,689 CHARS

BACKGROUND

Vitamin D (VitD) and its receptor (VDR) are implicated in cancer, but their role in head and neck squamous cell carcinomas (HNC) is poorly understood. This study aimed to assess the clinical and preclinical relevance of the VDR/VitD axis in HNC. Methods: The study combined analysis of a clinical cohort (40 HNC patients, 40 healthy controls) with bioinformatic analysis of TCGA data (n=604) and in vitro experiments using HNC cell lines and 3D tumor spheroids. Key Results: In the clinical cohort, serum VitD levels were lowest in poorly differentiated tumors (4.1 ± 0.5 ng/mL) and highest in well-differentiated tumors (13.2 ± 3.4 ng/mL). VDR expression was inversely correlated with VitD levels and was high in poorly differentiated tumors. TCGA analysis confirmed VDR overexpression in HNC tumors, correlating with histological differentiation and HPV-negative status. In vitro, VitD induced VDR nuclear translocation and synergistically enhanced cisplatin-mediated killing of HNC cells (combination index <1). This synergy was confirmed in 3D tumor spheroids, where VitD alone also impaired spheroid formation. Mechanistically, VitD/cisplatin combination downregulated phosphorylated mTOR and Akt. Limitations: The clinical cohort is small (n=40) and geographically specific (Egypt), which may affect generalizability. The study does not provide long-term patient survival data. Implications: The findings suggest that VDR/VitD-targeted combinations, particularly with cisplatin, warrant further investigation for HNC. Gender-specific effects and socioeconomic factors influencing VitD levels should be considered in future studies and potential supplementation therapies.

PICO

PPOPULATION

Patients with head and neck squamous cell carcinomas (HNC) (n=40) and healthy controls (n=40); HNC cell lines (FaDu, HNCUM-02T, Pica, etc.)

IINTERVENTION

Vitamin D (VitD) treatment, alone or in combination with cisplatin

OOUTCOME

VDR expression, serum VitD levels, tumor differentiation, cell viability, spheroid formation, mTOR/PI3K-Akt pathway activity

STUDY TYPE

other

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10002563

Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck

International Journal of Molecular Sciences

READ THE FULL PAPER

JUMP TO SECTION

ABSTRACT

Vitamin D (VitD) and its receptor (VDR) have been intensively investigated in many cancers. As knowledge for head and neck cancer (HNC) is limited, we investigated the (pre)clinical and therapeutic relevance of the VDR/VitD-axis. We found that VDR was differentially expressed in HNC tumors, correlating to the patients’ clinical parameters. Poorly differentiated tumors showed high VDR and Ki67 expression, whereas the VDR and Ki67 levels decreased from moderate to well-differentiated tumors. The VitD serum levels were lowest in patients with poorly differentiated cancers (4.1 ± 0.5 ng/mL), increasing from moderate (7.3 ± 4.3 ng/mL) to well-differentiated (13.2 ± 3.4 ng/mL) tumors. Notably, females showed higher VitD insufficiency compared to males, correlating with poor differentiation of the tumor. To mechanistically uncover VDR/VitD’s pathophysiological relevance, we demonstrated that VitD induced VDR nuclear-translocation (VitD < 100 nM) in HNC cells. RNA sequencing and heat map analysis showed that various nuclear receptors were differentially expressed in cisplatin-resistant versus sensitive HNC cells including VDR and the VDR interaction partner retinoic acid receptor (RXR). However, RXR expression was not significantly correlated with the clinical parameters, and cotreatment with its ligand, retinoic acid, did not enhance the killing by cisplatin. Moreover, the Chou–Talalay algorithm uncovered that VitD/cisplatin combinations synergistically killed tumor cells (VitD < 100 nM) and also inhibited the PI3K/Akt/mTOR pathway. Importantly, these findings were confirmed in 3D-tumor-spheroid models mimicking the patients’ tumor microarchitecture. Here, VitD already affected the 3D-tumor-spheroid formation, which was not seen in the 2D-cultures. We conclude that novel VDR/VitD-targeted drug combinations and nuclear receptors should also be intensely explored for HNC. Gender-specific VDR/VitD-effects may be correlated to socioeconomic differences and need to be considered during VitD (supplementation)-therapies.

CITATION EXPORT

Laura Koll, Désirée Gül, Manal I. Elnouaem et al.. Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms24054675

AUTHORS

10 · 4 CENTRES

Laura Koll, Désirée Gül, Manal I. Elnouaem, Hanaa Raslan, Omneya R. Ramadan, Shirley K. Knauer, Sebastian Strieth, Jan Hagemann, Roland H. Stauber, Aya Khamis

1Department of Otorhinolaryngology Head and Neck Surgery, Molecular and Cellular Oncology, University Medical Center, 55131 Mainz, Germany
2Oral Pathology Department, Faculty of Dentistry, Alexandria University, Alexandria 5372066, Egypt
3Centre for Medical Biotechnology (ZMB/CENIDE), Institute for Molecular Biology, University Duisburg-Essen, Universitätsstraße, 45117 Essen, Germany
4Department of Otorhinolaryngology, University Medical Center Bonn, 53127 Bonn, Germany

EDITOR / REVIEWER

Eric Parkinson