Policing Cancer: Vitamin D Arrests the Cell Cycle

Abstract

Vitamin D is a steroid hormone crucial for bone mineral metabolism. In addition, vitamin D has pleiotropic actions in the body, including anti-cancer actions. These anti-cancer properties observed within in vitro studies frequently report the reduction of cell proliferation by interruption of the cell cycle by the direct alteration of cell cycle regulators which induce cell cycle arrest. The most recurrent reported mode of cell cycle arrest by vitamin D is at the G1/G0 phase of the cell cycle. This arrest is mediated by p21 and p27 upregulation, which results in suppression of cyclin D and E activity which leads to G1/G0 arrest. In addition, vitamin D treatments within in vitro cell lines have observed a reduced C-MYC expression and increased retinoblastoma protein levels that also result in G1/G0 arrest. In contrast, G2/M arrest is reported rarely within in vitro studies, and the mechanisms of this arrest are poorly described. Although the relationship of epigenetics on vitamin D metabolism is acknowledged, studies exploring a direct relationship to cell cycle perturbation is limited. In this review, we examine in vitro evidence of vitamin D and vitamin D metabolites directly influencing cell cycle regulators and inducing cell cycle arrest in cancer cell lines.

Keywords: anti-proliferation; calcitriol; cancer; cell cycle; cell proliferation; cyclin-dependent kinase; cyclin-dependent kinase inhibitor; vitamin D.

Figure 1

The cell cycle phases and key regulatory checkpoints in eukaryotes. Cells cycle through Gap1 (G1), Gap2 (G2), DNA synthesis (S), and mitosis (M) phases. Cells may temporarily exit the cell cycle at the G1/G0 transition point in response to high cell density or mitogen deprivation. Three cell cycle checkpoints regulate sequential progression between the phases. Regulatory proteins (cyclins) pair with specific catalytic subunits (cyclin-dependent kinases) to form an active kinase that drives cell progression through the restriction point (R). (Abbreviations: G1: Gap1; G2: Gap2; S: Synthesis phase; M; Mitosis; CDK: cyclin-dependent kinase). (Source: personal collection)

Figure 2

Calcitriol upregulates p21 and p27 expression in the G1 phase and prevents cell cycle progression to the S phase [3]. Calcitriol (1,25(OH)₂D₃) increases the expression of CDK inhibitors (CDKIs), p21 and p27, by numerous mechanisms. p21 expression is increased by stimulation of liganded VDR signaling. p27 expression is increased by signaling transcription factors; inhibition of p27 protein degradation by S-phase kinase-associated protein 2 (Skp2); and enhanced p27 translation by abrogated microRNA-181a expression. The collective outcome of the increased CDKI expression is suppression of cyclin-CDK complex formation, which inhibits the formation of hyperphosphorylated retinoblastoma protein (pRB). The unphosphorylated pRB thus is able to form a repressor complex with histone deacetylase (HDAC) and E2F transcription factor (E2F), which prevents the progression of cancer cells in the G1 phase to the S phase, inhibiting S phase gene expression, and thus causing G0/G1 cell cycle arrest. (Source: personal collection).