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Review
. 2017 Oct 19;18(10):2184.
doi: 10.3390/ijms18102184.

Vitamin D as a Novel Regulator of Tumor Metabolism: Insights on Potential Mechanisms and Implications for Anti-Cancer Therapy

Mohamed A Abu El Maaty  1 , Stefan Wölfl  2
Affiliations
Review

Vitamin D as a Novel Regulator of Tumor Metabolism: Insights on Potential Mechanisms and Implications for Anti-Cancer Therapy

Mohamed A Abu El Maaty et al. Int J Mol Sci. .

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.

Keywords: AMPK (AMP-activated protein kinase); HIF1a (Hypoxia-inducible factor 1a); TXNIP (Thioredoxin-interacting protein); autophagy; c-Myc; cancer; mTOR (Mammalian target of rapamycin); metabolism; p53; vitamin D.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multi-level regulation of the AMPK-mTOR-TXNIP signaling triad by 1,25(OH)2D3 and potential impact on metabolism. Induction of AMPK signaling by 1,25(OH)2D3, through increasing the AMP:ATP ratio or intracellular Ca2+ levels, may lead to differential TXNIP regulation. On one hand, AMPK directly phosphorylates TXNIP and marks it for degradation. On the other hand, AMPK activation may lead to an increase in TXNIP levels, through increasing the availability of the TXNIP-regulating transcriptional machinery, namely MondoA (not depicted in figure), as a result of mTOR signaling inhibition. mTOR inhibition secondary to AMPK activation is achieved by two mechanisms: (i) through phosphorylating TSC2 (tuberous sclerosis complex 2), which inhibits the activity of the mTOR stimulator Rheb (Ras homologue enriched in brain), and (ii) through phosphorylating Raptor (regulatory-associated protein of mTOR), thereby inhibiting mTOR complex 1 (mTORC1) activity. Additionally, calcitriol may also inhibit mTOR signaling through inducing the expression of DDIT4, which enables the assembly/activation of TSC1/2. This may lead to an increase in TXNIP levels, which in turn could inhibit mTOR signaling through stabilizing DDIT4. It is, however, unclear whether 1,25(OH)2D3 directly regulates TXNIP expression or not (hence this action is depicted using a dashed line). Furthermore, the induction of glucose uptake by AMPK activation conflicts with the demonstrated ability of 1,25(OH)2D3 to reduce the expression of GLUT1 in cancer cells. Moreover, the induction of autophagy by VDR activators has been shown to involve AMPK signaling, as well as the direct regulation of autophagy genes. We propose that calcitriol treatment regulates energy utilization of cancer cells through multiple mechanisms, including the regulation of the AMPK-mTOR-TXNIP triad. Arrows indicate induction and blunted arrows (T bar) indicate inhibition.
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