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Review
. 2022 Jun;179(12):2890-2905.
doi: 10.1111/bph.15424. Epub 2021 Apr 8.

Vitamin D regulation of energy metabolism in cancer

Madeline P Sheeley  1 , Chaylen Andolino  1 , Violet A Kiesel  1 , Dorothy Teegarden  1
Affiliations
Review

Vitamin D regulation of energy metabolism in cancer

Madeline P Sheeley et al. Br J Pharmacol. 2022 Jun.

Abstract

Vitamin D exerts anti-cancer effects in recent clinical trials and preclinical models. The actions of vitamin D are primarily mediated through its hormonal form, 1,25-dihydroxyvitamin D (1,25(OH)2 D). Previous literature describing in vitro studies has predominantly focused on the anti-tumourigenic effects of the hormone, such as proliferation and apoptosis. However, recent evidence has identified 1,25(OH)2 D as a regulator of energy metabolism in cancer cells, where requirements for specific energy sources at different stages of progression are dramatically altered. The literature suggests that 1,25(OH)2 D regulates energy metabolism, including glucose, glutamine and lipid metabolism during cancer progression, as well as oxidative stress protection, as it is closely associated with energy metabolism. Mechanisms involved in energy metabolism regulation are an emerging area in which vitamin D may inhibit multiple stages of cancer progression. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

Keywords: Vitamin D; cancer; glucose; glutamine; lipids; metabolism; oxidative Stress.

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Figures

FIGURE 1
FIGURE 1
Overview of vitamin D metabolism and transcriptional effects within cancer cells. The most active vitamin D metabolite, 1,25 (OH)2D, is synthesized in the body following two hydroxylation events. This metabolite binds the vitamin D receptor to induce heterodimerization to retinoid X receptor, which subsequently binds to the vitamin D response element within the promoter region of vitamin D target genes. A number of different gene families are regulated by 1,25(OH)2D, including those involved in apoptosis and cell cycle arrest, as well as cell metabolism. Generally, 1,25(OH)2D downregulates a variety of genes involved in glucose, glutamine and lipid metabolism, as well as oxidative stress protection. Additional studies are needed (indicated by “?”) to connect these mechanisms to cancer-related outcomes involved in cancer progression. Abbreviations: 25(OH)D-25—hydroxyvitamin D; 1,25(OH)2D-1α,25—dihydroxyvitamin D; VDR—vitamin D receptor; RXR—retinoid X receptor; VDRE—vitamin D response element
FIGURE 2
FIGURE 2
Decreased glucose metabolism mediated by 1,25(OH)2D. An overall reduction in glycolysis and glucose entry into the TCA cycle is observed in cancer cells treated with the active metabolite of vitamin D, 1,25 (OH)2D. Treatment of cancer cells in vitro with 1,25(OH)2D results in reduced enzyme expression or activity (red font) and [U-13C]-glucose flux to metabolites (red shaded boxes). Abbreviations: 1,25 (OH)2D-1,25—dihydroxyvitamin D; [U-13C]—universally labelled carbon 13; GLUT1—glucose transporter 1; HK2—hexokinase 2; G6P—glucose-6-phosphate; 3PG—3-phosphoglycerate; LDHA—lactate dehydrogenase A; PDK1—pyruvate dehydrogenase kinase 1; PDH—pyruvate dehydrogenase; PC—pyruvate carboxylase; OAA—oxaloacetate; TCA—tricarboxylic acid
FIGURE 3
FIGURE 3
Decreased glutamine metabolism mediated by 1,25 (OH)2D. A decrease in glutamine metabolism and replenishment of the TCA cycle by glutamine is observed in 1,25(OH)2D-treated cancer cells. Treatment of cancer cells in vitro with 1,25(OH)2D reduces enzyme expression or activity (red font) and [U-13C]-glutamine flux to metabolites (red shaded boxes). Abbreviations: 1,25 (OH)2D-1,25—dihydroxyvitamin D; SLC1A5—solute carrier family 1 member 5; GLS—glutaminase; GLUL—glutamate ammonia ligase/glutamine synthetase; αKG-α—ketoglutarate; TCA—tricarboxylic acid
FIGURE 4
FIGURE 4
The regulation of lipid metabolism by 1,25(OH)2D. A decrease in palmitate synthesis (red shaded box) from glucose, through the downregulation of pyruvate carboxylase (red font), is observed in 1,25 (OH)2D treated breast cancer cells. Other in vitro studies indicate that 1,25(OH)2D reduces malonyl-CoA (red shaded box) and differentially affects (black and red arrows) fatty acid synthase as well as neutral lipid accumulation, depending on the type and stage of the cancer model. Abbreviations: 1,25(OH)2D-1α,25—dihydroxyvitamin D; CD36—cluster of differentiation 36; FATP—fatty acid transport protein; ACC—acetyl-CoA carboxylase; FASN—fatty acid synthase; PC—pyruvate carboxylase; OAA—oxaloacetate; TCA—tricarboxylic acid
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