Abstract
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the bioactive form of vitamin D, has been shown to possess significant anti-tumor potential. While most studies so far have focused on the ability of this molecule to influence the proliferation and apoptosis of cancer cells, more recent data indicate that 1,25(OH)2D3 also impacts energy utilization in tumor cells. In this article, we summarize and review the evidence that demonstrates the targeting of metabolic aberrations in cancers by 1,25(OH)2D3, and highlight potential mechanisms through which these effects may be executed. We shed light on the ability of this molecule to regulate metabolism-related tumor suppressors and oncogenes, energy- and nutrient-sensing pathways, as well as cell death and survival mechanisms such as autophagy.
Highlights
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the bioactive form of vitamin D, has been shown to possess significant anti-tumor potential
While most studies so far have focused on the ability of this molecule to influence the proliferation and apoptosis of cancer cells, more recent data indicate that 1,25(OH)2D3 impacts energy utilization in tumor cells
We summarize and review the evidence that demonstrates the targeting of metabolic aberrations in cancers by 1,25(OH)2D3, and highlight potential mechanisms through which these effects may be executed
Summary
Normal cells efficiently break down glucose through multi-step processes, namely glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, to yield reducing equivalents and ATP [1]. The expression/activity of several “metabolic genes” have been shown to be altered in tumors, for example glucose transporter 1 (GLUT1) [4], pyruvate kinase M2 (PKM2) [5], as well as lactate dehydrogenase A (LDHA) [6], making them potential druggable targets The resurrection of this cancer hallmark has prompted investigations into diverse metabolism-related therapeutic options [7]. Besides aberrations in glucose metabolizing pathways, accumulating evidence has illustrated that cancer cells have an increased demand for different amino acids, most notably glutamine, known as the phenomenon of “glutamine addiction” [10] These amino acids are required, for example, in TCA cycle anaplerosis, the conversion of glutamine to glutamic acid and α-ketoglutarate by the enzymes glutaminase and glutamic acid dehydrogenase [10], respectively, as well as for the maintenance of the redox balance and anabolic processes, e.g., serine, through contribution to the folate cycle [11]. In addition to the aforementioned drugs, accumulating evidence has pointed towards the ability of the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] ( known as calcitriol), to influence energy utilization in cancer cells [14,15,16,17]
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