The role of vitamin D in head and neck cancer

Abstract

Objective: Head and neck squamous cell carcinoma (HNSCC) describes a set of malignancies of the head and neck that continue to inflict considerable morbidity and mortality. Because HNSCC often presents at an advanced stage, patients frequently undergo intensive multi-modal therapy with an intent to cure. Vitamin D is a precursor to the biologically active hormone calcitriol which governs bone and calcium physiology that is obtained from diet and UV-B exposure. Vitamin D is known to have pleiotropic effects on health and disease. In this review, we examine the role of vitamin D in cancer with emphasis on HNSCC and discuss potential avenues for further research that might better elucidate the role of vitamin D in the management of HNSCC.

Review methods: A review of MEDLINE database indexed literature concerning the role and biology of vitamin D in HNSCC was conducted, with special consideration of recently published work and research involving immunobiology and HNSCC.

Conclusions: The available evidence suggests that vitamin D may play a role in protecting against HNSCC, particularly in persons who smoke, although conflicting and limited data exists. Promising initial work encourages the pursuit of further study.

Implications for practice: The significant morbidity and mortality that HNSCC brings warrants continued research in available and safe interventions that improve patient outcomes. With the rise of immunotherapy as an effective modality for treatment, continued research of vitamin D as an adjunct in the treatment of HNSCC is supported.

Keywords: clinical review; head and neck squamous cell carcinoma; immunotherapy; micronutrient; vitamin D.

FIGURE 1

Vitamin D metabolism and activity in cancer. A, Cholecalciferol is obtained through either skin exposure to UV‐B or diet. Cholecalciferol is converted to 25‐hydroxyvitamin D [25(OH)D)]via CYP27A1 activity in the liver. 25(OH)D is converted to calcitriol (1α,25(OH)2D) via CYP27B1 activity primarily in the kidney. Calcitriol is the active form of vitamin D and is the primary ligand for the vitamin D receptor (VDR). Vitamin D‐bound VDR heterodimerizes with RXR before translocating to the nucleus to engage VDR response elements and effect transcription. Vitamin D is metabolized for excretion by CYP24A1 which produces the inactive metabolite 24,25(OH)2D. B, Vitamin D via activation of VDR alters numerous cascades relevant to the pathophysiology of head and neck squamous cell carcinoma. Upregulation of the tumor suppressor Pten antagonizes PI3K‐AKT–mTOR signaling downstream of receptor tyrosine kinase (RTK) activation by growth factors. The pro‐apoptotic factors Bax and Bak are upregulated by vitamin D and prime cells for apoptosis, which is reinforced by the inhibition of the pro‐survival Bcl‐xL. Upregulation of p21 and p27 triggers inhibition of pRB phosphorylation and degradation by CDK complexes, thereby stabilizing the pRB‐E2F1 complex and inhibiting E2F1‐driven progression through the cell cycle. Vitamin D also antagonizes dedifferentiation and telomerase expression which limits malignancy. Upregulation of the master transcriptional regulator of the cellular antioxidant machinery, NRF2, promotes genomic stability and limits oxidative damage. NF‐κB is inhibited from translocating to the nucleus by vitamin D thereby reducing transcription of pro‐inflammatory cytokines including IL‐6 and TNF‐α. Vitamin D also downregulates prostaglandin (PG) synthesis via inhibition of cyclooxygenase‐2 (COX‐2). Lastly, the expression of the PD‐L1 cell surface glycoprotein, which acts as a mediator of peripheral tolerance and attenuator of T cell activation, is up‐regulated by VDR activation. Solid black arrows represent positive interactions, hatched black arrows represent actions inhibited downstream of vitamin D activity, and hammerhead arrows represent repressive interactions