Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells.

Chun-Yin Huang,Yu-Ting Weng,Po-Chen Li,Hsiao-Sheng Liu,Nien-Tsu Hsieh,Chun-I Li,Ming-Fen Lee

doi:10.3390/life11090963

Abstract

Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D3), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the “Warburg effect” to support cell growth by upregulating glycolysis, and the glycolytic intermediates further serve as building blocks to generate biomass. The objective of the current study is to investigate whether calcitriol affects glucose metabolism and cell growth in human colorectal cancer cells. Calcitriol reduced the expression of cyclin D1 and c-Myc. In addition, calcitriol reduced the expression of glucose transporter 1 (GLUT1) and key glycolytic enzymes and decreased extracellular acidification rate but increased oxygen consumption rate in human colorectal cancer cells. In a subcutaneous HT29 xenograft NOD/SCID mouse model, the volume and weight of the tumors were smaller in the calcitriol groups as compared with the control group, and the expression levels of GLUT1 and glycolytic enzymes, hexokinase 2 and lactate dehydrogenase A, were also lower in the calcitriol groups in a dose-responsive manner. Our data indicate that calcitriol suppresses glycolysis and cell growth in human colorectal cancer cells, suggesting an inhibitory role of the biologically active form of vitamin D in colorectal cancer progression.

Highlights

Vitamin D, an essential nutrient responsible for calcium homeostasis, exhibits important extraskeletal, noncalcemic functions [1]
We found that calcitriol inhibited cell growth and suppressed the expression of glucose transporter 1 (GLUT1) and glycolytic proteins in human colorectal cancer cells in vitro and in vivo, indicating a protective role of calcitriol in colorectal cancer
There was no statistical difference in cell viability up to 100 nM, whereas 500 nM and above of calcitriol treatment resulted in cell death in both HT29 and

Summary

Introduction

Vitamin D, an essential nutrient responsible for calcium homeostasis, exhibits important extraskeletal, noncalcemic functions [1]. (1,25(OH) D3 ), the biologically active form of vitamin D, exerts pleiotropic genomic and nongenomic actions [2]. Vitamin D often exerts its effect through the vitamin D receptor (VDR), a nuclear receptor superfamily member, by interacting with other transcription factors [3]. Calcitriol interacts with VDR, which heterodimerizes with retinoid X receptors (RXRs). The complex translocates into the nucleus and binds to the vitamin D response element (VDRE) in the promoters of the target genes to regulate gene expression. Calcitriol transduces signals through related nuclear receptor members and regulates many common aspects of physiological function, including cell growth and differentiation in epithelial tissues and the immune system [2,4].

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