title: Diallyl disulfide inhibits TNFα induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling.
abstract: TNFα receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFκB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFα induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFα mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFα initiates a rise in NFκB mRNA, which is not reversed by DADS. However, TNFα induced heightened expression of IKKε and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFα was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFα invoked CCL2 production primarily through reduction of IKKε and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFκB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFα surface receptors.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bauer
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: N
authors.initials: N
authors.lastname: Redmon
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mazzio
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: E
authors.initials: E
authors.lastname: Taka
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Reuben
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: A
authors.initials: A
authors.lastname: Day
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sadrud-Din
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: H
authors.initials: H
authors.lastname: Flores-Rozas
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: K F A
authors.initials: KF
authors.lastname: Soliman
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. Electronic address: selina.darling@famu.edu.
authors.forename: S
authors.initials: S
authors.lastname: Darling-Reed
mesh_terms: D000498:Allyl Compounds / Q000737:chemistry*; D000873:Anthracenes / Q000737:chemistry; D016588:Anticarcinogenic Agents / Q000737:chemistry; D002070:Butadienes / Q000737:chemistry; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry*; D005737:Garlic / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009570:Nitriles / Q000737:chemistry; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000498:Allyl Compounds; D000873:Anthracenes; D016588:Anticarcinogenic Agents; D002070:Butadienes; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004220:Disulfides; D007093:Imidazoles; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009570:Nitriles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C432165:pyrazolanthrone; C028009:diallyl disulfide; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
keywords: Diallyl disulfide; Map kinase b; Monocyte chemoattractant protein 1; Nuclear factor kappa b; Tumor necrosis factor alpha