Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

Seidel, Petra; Merfort, Irmgard; Hughes, JM; Oliver, Brian G.; Tamm, Michael; Roth, Michael

doi:10.1152/ajplung.90624.2008

Cited by 79 publications

(102 citation statements)

References 48 publications

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“…Previous reports have suggested that, upon DMF treatment, phosphorylation of NFB transcription factors and subsequent nuclear translocation are attenuated (26,52). This occurs in an IKK/IB␣-independent manner and via other kinases, such as MSK-1, which phosphorylates p65 at Ser-468 (24,26,52). In agreement with these reports, we found that, in breast cancer cells, DMF reduces the nuclear content of phosphorylated and total p65 in an IKK/IB␣-independent manner.…”

Section: Discussionmentioning

confidence: 93%

“…Besides NFB inhibition, DMF has also been proposed to activate Nrf2 (23)(24)(25)(26). Indeed, we found that DMF significantly up-regulates the Nrf2 target gene, heme oxygenase 1 (HMOX1) mRNA, both in 2D and in MS (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although DMF is an approved immune-modulatory drug that has been shown to inhibit NFB signaling in a variety of cell lines and tissues (23)(24)(25)(26)52), the activity in breast cancer cells was unknown, and the specific mechanism of action with respect to the NFB pathway was unclear. Previous reports have suggested that, upon DMF treatment, phosphorylation of NFB transcription factors and subsequent nuclear translocation are attenuated (26,52).…”

Section: Discussionmentioning

confidence: 99%

“…DMF was approved in the United States in March 2013 for multiple sclerosis and is now the number one prescribed oral therapy for relapsing forms of the disease. DMF is neuroprotective and is proposed to act via inhibition of NFB and activation of Nrf2 pathways (23)(24)(25)(26). Most importantly, DMF has a proven safety in humans; it has immune-modulatory properties without significant immune suppression (27).…”

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confidence: 99%

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

Kastrati

Siklos

Calderon-Gierszal

et al. 2016

Journal of Biological Chemistry

120

102

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In breast tumors, activation of the nuclear factor B (NFB) 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-NFB 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 NFB pathway. We found that DMF effectively blocks NFB activity in multiple breast cancer cell lines and abrogates NFB-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 NFB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFB activity. Also, the cell-permeable thiol N-acetyl L-cysteine, reverses DMF inhibition of the NFB 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 NFB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.In the United States, breast cancer is the second most prevalent cancer among women and claims over 40,000 lives each year. Despite major advancements in breast cancer treatment, a successful therapy outcome is limited to early detection of cancer at the primary organ. Therapy options for aggressive breast cancer disease (i.e. advanced stage, therapy-resistant, recurrent, or metastatic) are limited. As a result, the prognosis remains poor, and aggressive disease accounts for more than 90% of breast cancer-related deaths.Although the underlying mechanisms are not fully understood, inflammation has emerged as a key instigator and driver of aggressive breast cancers (1, 2). More specifically, the nuclear factor B (NFB) 2 pathway promotes multiple aggressive tumor phenotypes, including cell survival, migration, invasion, angiogenesis, and resistance to therapy (3, 4). The link between the inflammatory NFB pathway and breast cancer is also supported by the fact that a deregulated, or constitutively active, NFB pathway is associated with aggressive breast cancer phenotypes and therapy resistance (5-9). More recently, activation of the NFB pathway has been shown to regulate the survival and propagation of breast cancer stem cells (CSCs) (10 -12), which are a small subset of tumor cells that evade all standar...

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Kastrati

Siklos

Calderon-Gierszal

et al. 2016

Journal of Biological Chemistry

120

102

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“…GTCpFE is an effective NFĸB inhibitor, whereas ASA itself is not, even at much higher concentrations. The fumarate moiety has anti-inflammatory properties as shown by its ability to inhibit NFĸB signaling in a variety of cell lines and tissues 14,[25][26][27][28][29] . The prodrug strategy described herein, is amendable to other malignancies where multiple inflammatory pathways are active and contribute to the pathology.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

Kastrati

Delgado-Rivera

Georgieva

et al. 2017

JoVE

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Inflammation is a cancer hallmark that underlies cancer incidence and promotion, and eventually progression to metastasis. Therefore, adding an anti-inflammatory drug to standard cancer regiments may improve patient outcome. One such drug, aspirin (acetylsalicylic acid, ASA), has been explored for cancer chemoprevention and anti-tumor activity. Besides inhibiting the cyclooxygenase 2-prostaglandin axis, ASA's anticancer activities have also been attributed to nuclear factor ĸB (NFĸB) inhibition. Because prolonged ASA use may cause gastrointestinal toxicity, a prodrug strategy has been implemented successfully. In this prodrug design the carboxylic acid of ASA is masked and additional pharmacophores are incorporated.This protocol describes how we synthesized an aspirin-fumarate prodrug, GTCpFE, and characterized its inhibition of the NFĸB pathway in breast cancer cells and attenuation of the cancer stem-like properties, an important NFĸB-dependent phenotype. GTCpFE effectively inhibits the NFĸB pathway in breast cancer cell lines whereas ASA lacks any inhibitory activity, indicating that adding fumarate to ASA structure significantly contributes to its activity. In addition, GTCpFE shows significant anti-cancer stem cell activity by blocking mammosphere formation and attenuating the cancer stem cell associated CD44 + CD24-immunophenotype. These results establish a viable strategy to develop improved anti-inflammatory drugs for chemoprevention and cancer therapy.

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PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

et al. 2020

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Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2-Del2, which is devoid of the tumor-suppressive function of full-length PDSS2 (PDSS2-FL). To better understand the clinical significance of PDSS2-Del2, we performed a BaseScope assay on an HCC tissue microarray and found that positive staining for PDSS2-Del2 predicted a worse overall survival in patients with HCC (P=0.02). PDSS2-Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2-Del2 overexpression functionally promoted HCC metastasis as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2-Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2-Del2 expression in HCC tumor cells decreased fumarate levels and activated canonical NF-κB pathway. The epithelial-to-mesenchymal transition (EMT) and WNT/β-catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2-Del2 as observed with in vivo spleen-liver metastasis animal experiments. Considering that DMF is a prescribed oral therapy for multiple sclerosis, it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.

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Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

Abstract: Seidel P, Merfort I, Hughes JM, Oliver BG, Tamm M, Roth M. Dimethylfumarate inhibits NF-B function at multiple levels to limit airway smooth muscle cell cytokine secretion.

Cited by 79 publications

References 48 publications

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

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

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

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Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

Abstract: Seidel P, Merfort I, Hughes JM, Oliver BG, Tamm M, Roth M. Dimethylfumarate inhibits NF-B function at multiple levels to limit airway smooth muscle cell cytokine secretion.

Cited by 79 publications

References 48 publications

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

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

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NF&#954;B Activity and Breast Cancer Stem Cells

PDSS2‐Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF‐κB

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Resources

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Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells