Abstract
All-trans retinoic acid (ATRA) is an effective drug for the induction therapy of acute promyelocytic leukemia. However, the treatment is associated with adverse events such as retinoic acid syndrome (RAS) in some patients, whose histologic characteristics included organ infiltration by leukemic cells. Matrix metalloproteinase 2 (MMP-2) is often upregulated in tumor cells and plays a role in tumor cell migration and invasion by degrading the extracellular matrix. In this study, we examined the possible modulatory effects of ATRA on MMP-2 expression and secretion in human myeloid leukemia cell line THP-1. The cells were treated with various concentrations of ATRA, and MMP-2 expression and secretion were examined. MMP-2 expression and secretion started to increase with ATRA concentration as low as 0.1 nM and gradually increased thereafter. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) alone could enhance MMP-2 secretion, and RAR or RXR antagonists alone could reverse ATRA-induced MMP-2 secretion. ATRA increased intracellular calcium ion levels, and a calcium-channel blocker inhibited ATRA-induced MMP-2 secretion. Dexamethasone suppressed ATRA-induced MMP-2 secretion. Our results suggest that ATRA enhances MMP-2 expression and secretion in human myeloid leukemia THP-1 cells in a calcium ion dependent manner through RAR/RXR signaling pathways, and this enhanced expression and secretion may be associated with the possible mechanisms of RAS.
Highlights
All-trans retinoic acid (ATRA) is the most abundant physiologically active metabolite of vitamin A
This translocation leads to the fusion of the retinoic acid receptor-α (RARα) gene and promyelocytic leukemia (PML) gene, resulting in the formation of the PML/RAR-α fusion protein, which is involved in leukemogenesis [6, 7]
We examined the effects of ATRA on Matrix metalloproteinase 2 (MMP-2) expression in the human myeloid leukemic cell line THP-1
Summary
All-trans retinoic acid (ATRA) is the most abundant physiologically active metabolite of vitamin A. It plays important roles in a wide range of biological processes such as the immune response and cell growth, differentiation, and apoptosis [1, 2]. ATRA has been used as an effective drug in the induction treatment of acute promyelocytic leukemia (APL) [3, 4]. APL is characterized by a reciprocal balanced translocation between chromosomes 15 and 17 [5] This translocation leads to the fusion of the retinoic acid receptor-α (RARα) gene and promyelocytic leukemia (PML) gene, resulting in the formation of the PML/RAR-α fusion protein, which is involved in leukemogenesis [6, 7]. In addition to its therapeutic usefulness in APL, ATRA has recently attracted great attention for the treatment of other cancers because of its antiproliferative and proapoptotic properties [9]
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