ACSL1 Regulates TNFα-Induced GM-CSF Production by Breast Cancer MDA-MB-231 Cells

Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in different types of cancer is associated with tumor growth and progression. Tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we investigated the role of ACSL1 in the TNF alpha mediated production of GM-CSF. Our results showed that MDA-MB-231 cells displayed increased GM-CSF mRNA expression and secretion after incubation with TNF alpha. Blocking of ACSL1 activity in the cells with triacsin C markedly suppressed the secretion of GM-CSF. However, inhibition of beta-oxidation and ceramide biosynthesis were not required for GM-CSF production. By small interfering RNA mediated knockdown, we further demonstrated that TNF alpha induced GM-CSF production was significantly diminished in ACSL1 deficient cells. TNF alpha mediated GM-CSF expression was significantly reduced by inhibition of p38 MAPK, ERK1/2 and NF-kappa B signaling pathways. TNF alpha induced phosphorylation of p38, ERK1/2, and NF-kappa B was observed during the secretion of GM-CSF. On the other hand, inhibition of ACSL1 activity attenuates TNF alpha mediated phosphorylation of p38 MAPK, ERK1/2, and NF-kappa B in the cells. Importantly, our findings suggest that ACSL1 plays an important role in the regulation of GM-CSF induced by TNF alpha in MDA-MB-231 cells. Therefore, ACSL1 may be considered as a potential novel therapeutic target for tumor growth.