Journal article
Nitro-fatty acid inhibition of triple-negative breast cancer cell viability, migration, invasion, and tumor growth
The Journal of biological chemistry, Vol.293(4), pp.1120-1137
01/26/2018
DOI: 10.1074/jbc.M117.814368
PMCID: PMC5787792
PMID: 29158255
Abstract
Triple-negative breast cancer (TNBC) comprises ∼20% of all breast cancers and is the most aggressive mammary cancer subtype. Devoid of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2), that define most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies. Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO
-OA), were investigated in multiple preclinical models of TNBC. NO
-OA reduced TNBC cell growth and viability
, attenuated TNFα-induced TNBC cell migration and invasion, and inhibited the tumor growth of MDA-MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The up-regulation of these aggressive tumor cell growth, migration, and invasion phenotypes is mediated in part by the constitutive activation of pro-inflammatory nuclear factor κB (NF-κB) signaling in TNBC. NO
-OA inhibited TNFα-induced NF-κB transcriptional activity in human TNBC cells and suppressed downstream NF-κB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 and urokinase-type plasminogen activator. The mechanisms accounting for NF-κB signaling inhibition by NO
-OA in TNBC cells were multifaceted, as NO
-OA (
) inhibited the inhibitor of NF-κB subunit kinase β phosphorylation and downstream inhibitor of NF-κB degradation, (
) alkylated the NF-κB RelA protein to prevent DNA binding, and (
) promoted RelA polyubiquitination and proteasomal degradation. Comparisons with non-tumorigenic human breast epithelial MCF-10A and MCF7 cells revealed that NO
-OA more selectively inhibited TNBC function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, including a more favorable thiol/disulfide balance, greater extents of multidrug resistance protein-1 (MRP1) expression, and greater MRP1-mediated efflux of NO
-OA-glutathione conjugates. These observations reveal that electrophilic fatty acid nitroalkenes react with more alkylation-sensitive targets in TNBC cells to inhibit growth and viability.
Details
- Title: Subtitle
- Nitro-fatty acid inhibition of triple-negative breast cancer cell viability, migration, invasion, and tumor growth
- Creators
- Chen-Shan Chen Woodcock - University of PittsburghYi Huang - UPMC Hillman Cancer CenterSteven R Woodcock - University of PittsburghSonia R Salvatore - University of PittsburghBhupinder Singh - University of PittsburghFranca Golin-Bisello - University of PittsburghNancy E Davidson - Fred Hutch Cancer CenterCarola A Neumann - UPMC Hillman Cancer CenterBruce A Freeman - University of PittsburghStacy G Wendell - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(4), pp.1120-1137
- DOI
- 10.1074/jbc.M117.814368
- PMID
- 29158255
- PMCID
- PMC5787792
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Grant note
- R37 HL058115 / NHLBI NIH HHS P30 DK072506 / NIDDK NIH HHS R01 HL132550 / NHLBI NIH HHS P01 HL103455 / NHLBI NIH HHS R21 AI122071 / NIAID NIH HHS R01 HL058115 / NHLBI NIH HHS R01 HL064937 / NHLBI NIH HHS P30 CA047904 / NCI NIH HHS
- Language
- English
- Date published
- 01/26/2018
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383281202771
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