Abstract
The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.
Highlights
The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies
retinoic acid receptor (RAR) and retinoic acid responsive elements (RAREs) in both all-trans retinoic acid (ATRA)-sensitive and -resistant acute promyelocytic leukemia (APL) cells [55]. These results suggest that inhibiting histone deacetylase (HDAC) might sensitize APL cells to ATRA, which would be critical for patients who carry other variants of 17q chromosome translocation, such as promyelocytic leukemia zinc finger protein
The combination of calcitriol and glycogen synthase kinase 3 (GSK3) inhibitor induced phosphorylation at Ser208 of vitamin D receptor (VDR), resulting in enhanced VDR transcriptional activities and the activation of Jun NH2-terminal kinase (JNK) pathway [87]. These results suggest that vitamin D or its analogs can potentially be used as sensitizing agents in combination with other therapies to improve treatment outcomes for acute myeloid leukemia (AML) patients
Summary
The human nuclear receptor (NR) superfamily consists of 48 members that share highly evolutionarily conserved structures. Upon RA binding, RAR forms heterodimers with RXR and regulates downstream target genes through retinoic acid responsive elements (RAREs), which are characterized by two direct repeats of the sequence core motifs separated by nucleotides with various sizes [8]. The heterodimers of VDR/RXR bind to vitamin D responsive elements (VDREs), which contain direct or everted repeats of the sequence core motifs separated by three or six nucleotides [9]. Co-regulators function as members of large complexes, such as nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) These complexes regulate the transcription of target genes through interacting with other transcription factors and changing the chromatin landscape. NRs have been the therapeutic targets for many diseases, accounting for 10–15% of United States Food and Drug Administration (FDA)-approved therapeutic agents [18], especially for solid tumors such as breast cancer [19], lung cancer [20], and prostate cancer [21]
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