Abstract
The cell-microenvironment communication is essential for homing of hematopoietic stem cells in stromal niches. Recent evidences support the involvement of epithelial-to-mesenchymal (EMT) process in hematopoietic stem cell homeostasis as well as in leukemia cells invasiveness and migration capability. Here, we demonstrate that the alteration of iron homeostasis and the consequent increase of redox metabolism, mediated by the stable knock down of ferritin heavy chain (FtH), enhances the expression of CXCR4 in K562 erythroleukemia cells, thus promoting CXCL12-mediated motility. Indeed, addition of the CXCR4 receptor antagonist AMD3100 reverts this effect. Upon FtH knock down K562 cells also acquire an “EMT-like” phenotype, characterized by the increase of Snail, Slug and Vimentin with the parallel loss of E-cadherin. By using fibronectin as substrate, the cell adhesion assay further shows a reduction of cell adhesion capability in FtH-silenced K562 cells. Accordingly, confocal microscopy shows that adherent K562 control cells display a variety of protrusions while FtH-silenced K562 cells remain roundish. These phenomena are largely due to the reactive oxygen species (ROS)-mediated up-regulation of HIF-1α/CXCR4 axis which, in turn, promotes the activation of NF-κB and the enhancement of EMT features. These data are confirmed by treatments with either N-acetylcysteine (NAC) or AMD3100 or NF-κB inhibitor IκB-alpha which revert the FtH-silenced K562 invasive phenotype. Overall, our findings demonstrate the existence of a direct relationship among iron metabolism, redox homeostasis and EMT in the hematological malignancies. The effects of FtH dysregulation on CXCR4/CXCL12-mediated K562 cell motility extend the meaning of iron homeostasis in the leukemia cell microenvironment.
Highlights
The tumor microenvironment (TME) is a major player in cancer progression and several signals, such as oxygen supply, cytokines, and chemokines drive the communication between TME and tumor cells [1,2,3]
To assess the role of ferritin heavy chain (FtH) on CXCR4 signaling in hematological tumors, we first measured CXCR4 levels in K562shFtH and in K562shRNA and we found that FtH knock down significantly enhanced CXCR4 expression at both mRNA and protein levels (Figure 1A)
Tumor cell migration is a critical process that contributes to the development and progression of both solid and hematological malignancies [46, 47]
Summary
The tumor microenvironment (TME) is a major player in cancer progression and several signals, such as oxygen supply, cytokines, and chemokines drive the communication between TME and tumor cells [1,2,3]. The CXCL12/CXCR4 axis promotes tumor cell growth and propagation of distant metastases through the activation of epithelial-to-mesenchymal transition (EMT) [4]. Numerous studies have explored the role of ROS in inducing both cell migration and EMT in solid cancer [13, 14]. In this regard, we and others have previously reported that the knock down of ferritin heavy chain (FtH), the catalytic subunit of the human ferritin, promotes cell motility through either the activation of CXCR4 signaling or the induction of EMT in a variety of solid cancer in vitro models including breast and lung cancer cell lines [15,16,17]
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