All-Trans Retinoic Acid Enhances Matrix Metalloproteinase 2 Expression and Secretion in Human Myeloid Leukemia THP-1 Cells

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.

All-trans Retinoic Acid Induces Expression and Secretion of Carboxypeptidase D in THP-1 Cells

“…Similarly, our results revealed that the use of an RARα agonist moderately induces CPD protein expression, even at higher concentrations, whereas combined treatment with an RARα agonist and an RXRα agonist significantly induced CPD expression, suggesting that the RAR-RXR complex is required to induce the transcriptional activation of CPD expression. Similar to current observations, our previous study showed that ATRA enhances MMP-2 expression and secretion in THP-1 cells in an RAR/RXR-dependent manner (Vu et al, 2018).…”

“…*P < 0.05 vs. DMSO. Skidgel, 2001) and our previous study demonstrated that dexamethasone, an anti-inflammatory drug, inhibits ATRAinduced MMP-2 secretion in THP-1 cells (Vu et al, 2018), we tested whether this drug can also suppress ATRA-induced CPD expression and secretion in THP-1 cells. ATRAinduced enhancement of CPD mRNA expression ( Fig.…”

Carotenoids in Cancer Metastasis—Status Quo and Outlook

“…The inhibition of the Src-YAP-IL6 axis in both cell lines leads to reduced migration and invasion [21]. A similar pro-metastatic effect was observed in THP-1 human myeloid leukemia cells in which ATRA induced MMP-2 expression and secretion in a calcium ion-dependent manner, via the retinoic acid receptor (RAR) and retinoid X receptor (RXR) signaling pathways [22].…”

“…Despite the beneficial effects of carotenoids against metastasis in various cancer types, the use of carotenoids in some cases can lead to pro-invasive behavior, as demonstrated by ATRA use in cancer treatment [ 21 , 22 ]. Therefore, a more precise evaluation of carotenoid efficacy and the determination of detailed mechanisms can support a better understanding of carotenoids’ anti-cancer properties, especially in cancer prevention and therapy, for safe, efficient, and timely clinical trials.…”

“…However, despite the significant anti-metastatic efficacy of carotenoids, as demonstrated especially in preclinical research, specific carotenoids can exhibit rather pro-invasive tendencies (e.g., all-trans retinoic acid) [ 21 , 22 ]. Also, there is an unclear or rather negative association between carotenoids and lung or prostate cancer in specific parts of the population, e.g., smokers [ 23 , 24 ].…”