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Electrophilic Nitroalkenes Cause Degradation of NFκB RelA Protein in Triple Negative Breast Cancer Cells
Author(s) -
Woodcock ChenShan,
Woodcock Steven,
Davidson Nancy,
Huang Yi,
Freeman Bruce
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.945.8
Subject(s) - triple negative breast cancer , cancer research , survivin , estrogen receptor , cancer cell , cell growth , breast cancer , chemistry , viability assay , cyclin d1 , cancer , biology , cell , medicine , cell cycle , biochemistry
Triple negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR) and Her2/Neu, is an aggressive and metastatic cancer. Current therapy for TNBC is limited, and it is an unmet need for novel therapeutic agents with improved efficacy. Electrophilic fatty acids are endogenously‐generated signaling mediators that modulate cell differentiation and proliferation via post‐translational modification of nucleophilic amino acids (Cys, His) of transcriptional regulatory proteins such as NFkB, PPARgamma, and Keap1/Nrf2. Preliminary studies have revealed that an exemplary electrophilic fatty acid nitroalkene, nitro‐oleic acid (OA‐NO 2 ), displays potential therapeutic value in TNBC cells, by preferentially reducing the growth and viability of two human TNBC cell lines, but not normal breast cells. Essential to proliferation and survival, NFkB signaling is highly activated in ER‐negative breast cancer cells and primary tumors. Notably, NFkB RelA protein level was diminished in TNBC cells upon OA‐NO 2 treatment. Therefore, it is hypothesized that electrophilic fatty acids reduce TNBC cell proliferation and survival through down‐regulation of NFkB expression and signaling. We have demonstrated that OA‐NO 2 down‐regulates transcript levels of NFkB –regulated genes, cyclin D1 and the pro‐survival genes, bcl‐xL and survivin, in TNBC cells. Moreover, OA‐NO 2 promotes RelA protein polyubiquitination via nitroalkylation of RelA in TNBC cells. Overall, this study will serve as a prelude to the clinical study of electrophilic nitrated lipids as therapeutic agents that may display a high selectivity for killing TNBC tumors.