Vitamin D controls apoptosis and proliferation of cutaneous T‐cell lymphoma cells

Mrotzek, Christian; Felcht, Moritz; Sommer, Andrea; Schrader, Alexandra; Klemke, Claus‐Detlev; Herling, Marco; Schlaak, Max; Fabri, Mario

doi:10.1111/exd.12746

Cited by 6 publications

(11 citation statements)

References 8 publications

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“…Treatment of the MyLa cell line, a model of CTCL, with 25(OH)D 3 or calcitriol alone did not affect proliferation. However, a combination treatment of 25(OH)D 3 or calcitriol and bexarotene, an RXR agonist, inhibited proliferation (22). The role of vitamin D sufficient and insufficient levels was demonstrated in this experiment, as 33 nM of 25(OH)D 3 , representative of insufficient vitamin D, did not significantly increase apoptosis of the MyLa cell line or CTCL patient samples (22).…”

Section: Synergism With Anti-cancer Therapiesmentioning

confidence: 69%

“…However, a combination treatment of 25(OH)D 3 or calcitriol and bexarotene, an RXR agonist, inhibited proliferation (22). The role of vitamin D sufficient and insufficient levels was demonstrated in this experiment, as 33 nM of 25(OH)D 3 , representative of insufficient vitamin D, did not significantly increase apoptosis of the MyLa cell line or CTCL patient samples (22). A dose of 100 nM of 25(OH)D 3 was necessary to see effects, with greater apoptosis observed when bexarotene was added (22).…”

Section: Synergism With Anti-cancer Therapiesmentioning

confidence: 99%

“…Cutaneous T cell leukemia (CTCL) patients with either Sézary syndrome (SS) or mycosis fungoides also have low 25(OH)D 3 circulating levels, defined as less than sufficient levels, comparable to the decreased levels in patients with other cancers . Even when these patients were supplemented with vitamin D 2 or Vitamin D3, there was no observed difference in response to treatment .…”

Section: Vitamin D Serum Levelsmentioning

confidence: 99%

“…Of the subtypes of HL and B‐NHL examined, nodular lymphocyte predominant Hodgkin's lymphoma (NSHL) and DLBCL had the highest proportion of samples expressing VDR, respectively . B cell chronic lymphocytic leukemia (B‐CLL), CTCL with SS, and T cell large granular lymphocytic leukemia (T‐LGLL) cells were found to highly express VDR . On the contrary, VDR and CYP27B1 mRNA expression was decreased in tumor‐associated macrophages (TAMs) in Burkitt's lymphoma (BL) .…”

Section: Vitamin D Receptormentioning

confidence: 99%

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Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

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Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D 3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field.

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Section: Synergism With Anti-cancer Therapiesmentioning

confidence: 69%

Section: Synergism With Anti-cancer Therapiesmentioning

confidence: 99%

Section: Vitamin D Serum Levelsmentioning

confidence: 99%

Section: Vitamin D Receptormentioning

confidence: 99%

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Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

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“…Many hematological malignancies highly express VDR [47, 62, 63], suggesting a functional role for VDR in cancer cells. To explore the importance of VDR in T-LGLL, we utilized VDR siRNA to modulate VDR levels in order to replicate the varying levels found in patient cells [47].…”

Section: Discussionmentioning

confidence: 99%

Calcitriol-mediated reduction in IFN-γ output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation

Kulling

Olson

et al. 2018

The Journal of Steroid Biochemistry and Molecular Biology

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Constitutively activated STAT1 and elevated IFN-γ are both characteristic of T cell large granular lymphocytic leukemia (T-LGLL), a rare incurable leukemia with clonal expansion of cytotoxic T cells due to defective apoptosis. Interferon gamma (IFN-γ) is an inflammatory cytokine that correlates with worse progression and symptomology in multiple autoimmune diseases and cancers. In canonical IFN-γ-STAT1 signaling, IFN-γ activates STAT1, a transcription factor, via phosphorylation of tyrosine residue 701 (p-STAT1). p-STAT1 then promotes transcription of IFN-γ, creating a positive feedback loop. We previously found that calcitriol treatment of the TL-1 cell line, a model of T-LGLL, significantly decreased IFN-γ secretion and p-STAT1 while increasing the vitamin D receptor (VDR) protein. Here we further explore these observations. Using TL-1 cells, IFN-γ decreased starting at 4h following calcitriol treatment, with a reduction in the intracellular and secreted protein levels as well as the mRNA content. A similar reduction in IFN-γ transcript levels was observed in primary T-LGLL patient peripheral blood mononuclear cells (PBMCs). p-STAT1 inhibition followed a similar temporal pattern and VDR upregulation inversely correlated with IFN-γ levels. Using EB1089 and 25(OH)D, which have high or low affinity for VDR, respectively, we found that the decrease in IFN-γ correlated with the ability of EB1089, but not 25(OH)D, to upregulate VDR. However, both compounds inhibited p-STAT1; thus the reduction of p-STAT1 is not solely responsible for IFN-γ inhibition. Conversely, cells treated with VDR siRNA exhibited decreased basal IFN-γ production upon VDR knockdown in a dose-dependent manner. Calcitriol treatment upregulated VDR and decreased IFN-γ regardless of initial VDR knockdown efficiency, strengthening the connection between VDR upregulation and IFN-γ reduction. Our findings suggest multiple opportunities to further explore the clinical relevance of the vitamin D pathway and the potential role for vitamin D supplementation in T-LGLL.

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