Abstract
4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play an important role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibit phosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in human invasive breast cancer. Here we report that 4-HNE increased the cell growth of breast cancer cells as revealed by colony formation assay. Moreover, vascular endothelial growth factor (VEGF) expression was elevated, while protein levels of hypoxia inducible factor 1 alpha (HIF-1α) were up-regulated. Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, is reported to destabilize HIF-1α. Here, 4-HNE could inhibit the deacetylase activity of SIRT3 by thiol-specific modification. We further demonstrated that the regulation by 4-HNE of levels of HIF-1α and VEGF depends on SIRT3. Consistent with this, 4-HNE could not increase the cell growth in SIRT3 knockdown breast cancer cells. Additionally, 4-HNE promoted angiogenesis and invasion of breast cancer cells in a SIRT3-dependent manner. In conclusion, we propose that 4-HNE promotes growth, invasion and angiogenesis of breast cancer cells through the SIRT3-HIF-1α-VEGF axis.
Highlights
4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play an important role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibit phosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in human invasive breast cancer
The current study demonstrates that 4-HNE promoted the cell growth, invasion and angiogenesis of breast cancer cells. 4-HNE could up-regulate the expression and secretion of vascular endothelial growth factor (VEGF) in breast cancer cells
The enhancing effect of 4-HNE to the cell growth, invasion and angiogenesis of breast cancer cells was proved to depend on SIRT3
Summary
4-Hydroxynonenal (4-HNE) is the primary α/βunsaturated-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells (Patrick et al, 2005; Christov et al, 2013). 4-HNE can bind to cysteine, histidine, and lysine residues of proteins via Michael addition reaction (Bennaars-Eiden et al, 2002; Macpherson et al, 2007). 4-HNE can increase oxidative post translational modification (PTM) and alter protein function and cell signaling (Jin and Zangar, 2009; Ryan et al, 2014). HIF-1α protein is rapidly degraded and difficult to detect from cell lysates under normoxic conditions (Groulx and Lee, 2002) various factors can activate HIF-1α even under normoxic conditions and HIF-1α is detectable from isolated nuclei under normoxic conditions (Finley et al, 2011). This provides the possibility to study HIF-1α protein under normoxic conditions. We investigated the role of 4-HNE in the growth, invasion and angiogenesis of breast cancer
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