Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.

Article Details

Citation

Copy to clipboard

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	Unknown	Inhibitor Binder	Details

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