Abstract
Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in different types of cancer is associated with tumor growth and progression. Tumor necrosis factor-α (TNFα) is involved in the induction of GM-CSF in different cells; however, the underlying molecular mechanism in this production of GM-CSF has not been fully revealed. Recently, it was noted that TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we investigated the role of ACSL1 in the TNFα mediated production of GM-CSF. Our results showed that MDA-MB-231 cells displayed increased GM-CSF mRNA expression and secretion after incubation with TNFα. Blocking of ACSL1 activity in the cells with triacsin C markedly suppressed the secretion of GM-CSF. However, inhibition of β-oxidation and ceramide biosynthesis were not required for GM-CSF production. By small interfering RNA mediated knockdown, we further demonstrated that TNFα induced GM-CSF production was significantly diminished in ACSL1 deficient cells. TNFα mediated GM-CSF expression was significantly reduced by inhibition of p38 MAPK, ERK1/2 and NF-κB signaling pathways. TNFα induced phosphorylation of p38, ERK1/2, and NF-κB was observed during the secretion of GM-CSF. On the other hand, inhibition of ACSL1 activity attenuates TNFα mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB in the cells. Importantly, our findings suggest that ACSL1 plays an important role in the regulation of GM-CSF induced by TNFα in MDA-MB-231 cells. Therefore, ACSL1 may be considered as a potential novel therapeutic target for tumor growth.
Highlights
Granulocyte-macrophage colony-stimulating factor (GM-CSF), known as colony-stimulating factor 2 (CSF2), is a growth factor/cytokine which regulates the maturation and differentiation of hematopoietic cells [1]
Our data show (Figure 1A) that GM-CSF mRNA expression levels were significantly higher (14.02-fold; p < 0.001) in Tumor necrosis factor-α (TNFα)-treated MDA-MB-231 cells than those of controls
It is well established that overproduction of GM-CSF is involved in the pathogenesis of inflammatory diseases as well as tumor growth and progression [9,23]
Summary
Granulocyte-macrophage colony-stimulating factor (GM-CSF), known as colony-stimulating factor 2 (CSF2), is a growth factor/cytokine which regulates the maturation and differentiation of hematopoietic cells [1]. Dysregulation of GM-CSF is involved in chronic inflammatory diseases by the migration of myeloid cells to inflammation sites, sustaining the survival of target cells and promoting the renewal of macrophages [2]. In this context, a pathogenic role of elevated GM-CSF has been reported in autoimmune diseases that are dependent on cellular immune responses, such as multiple sclerosis (MS) and rheumatoid arthritis (RA) [3,4]. GM-CSF promotes cancer cell proliferation and migration in a wide variety of tumors and multiple cancer models In this connection, multiple cancer models show constitutive GM-CSF protein expression and secretion, often together with its conjugate receptors [9]. An increased level of GM-CSF in serum is considered as a potential diagnostic and prognostic marker for poor prognosis [10]
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