Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.
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Kastrati I, Siklos MI, Calderon-Gierszal EL, El-Shennawy L, Georgieva G, Thayer EN, Thatcher GR, Frasor J
Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.
J Biol Chem. 2016 Feb 12;291(7):3639-47. doi: 10.1074/jbc.M115.679704. Epub 2015 Dec 18.
- PubMed ID
- 26683377 [ View in PubMed]
- Abstract
In breast tumors, activation of the nuclear factor kappaB (NFkappaB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy--all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFkappaB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFkappaB pathway. We found that DMF effectively blocks NFkappaB activity in multiple breast cancer cell lines and abrogates NFkappaB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFkappaB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFkappaB activity. Also, the cell-permeable thiol N-acetyl l-cysteine, reverses DMF inhibition of the NFkappaB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFkappaB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dimethyl fumarate Transcription factor p65 Protein Humans UnknownInhibitorBinderDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Estradiol Approved Investigational Vet Approved IGFBP4 3487 upregulated Estradiol results in increased expression of IGFBP4 mRNA 17q21.2 Estradiol Approved Investigational Vet Approved TFF1 7031 upregulated Estradiol results in increased expression of TFF1 mRNA 21q22.3 Dimethyl fumarate Approved Investigational CCL2 6347 downregulated Dimethyl Fumarate results in decreased expression of CCL2 mRNA 17q12 Dimethyl fumarate Approved Investigational HMOX1 3162 upregulated Dimethyl Fumarate results in increased expression of HMOX1 mRNA 22q12.3 Dimethyl fumarate Approved Investigational ICAM1 3383 downregulated Dimethyl Fumarate results in decreased expression of ICAM1 mRNA 19p13.2 Dimethyl fumarate Approved Investigational TNF 7124 downregulated Dimethyl Fumarate results in decreased expression of TNF mRNA 6p21.33