title: 4-Hydroxynonenal promotes growth and angiogenesis of breast cancer cells through HIF-1α stabilization.
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.
authors.affiliation: Shanxi Breast Cancer Center, Shanxi Cancer Center, Taiyuan, China E-mail : yaopli@163.com.
authors.forename: Yao-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Fu-Guo
authors.initials: FG
authors.lastname: Tian
authors.forename: Peng-Cheng
authors.initials: PC
authors.lastname: Shi
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Guo
authors.forename: Hai-Ming
authors.initials: HM
authors.lastname: Wu
authors.forename: Run-Qi
authors.initials: RQ
authors.lastname: Chen
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Xue
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000378:metabolism; D061986:MCF-7 Cells; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C466093:SIRT3 protein, human; D056566:Sirtuin 3; C027576:4-hydroxy-2-nonenal