title: 3-Formylchromone interacts with cysteine 38 in p65 protein and with cysteine 179 in IκBα kinase, leading to down-regulation of nuclear factor-κB (NF-κB)-regulated gene products and sensitization of tumor cells.
abstract: 3-Formylchromone (3-FC) has been associated with anticancer potential through a mechanism yet to be elucidated. Because of the critical role of NF-κB in tumorigenesis, we investigated the effect of this agent on the NF-κB activation pathway. Whether activated by inflammatory agents (such as TNF-α and endotoxin) or tumor promoters (such as phorbol ester and okadaic acid), 3-FC suppressed NF-κB activation. It also inhibited constitutive NF-κB expressed by most tumor cells. This activity correlated with sequential inhibition of IκBα kinase (IKK) activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and reporter gene expression. We found that 3-FC inhibited the direct binding of p65 to DNA, and this binding was reversed by a reducing agent, thus suggesting a role for the cysteine residue. Furthermore, mutation of Cys38 to Ser in p65 abolished this effect of the chromone. This result was confirmed by a docking study. 3-FC also inhibited IKK activation directly, and the reducing agent reversed this inhibition. Furthermore, mutation of Cys179 to Ala in IKK abolished the effect of the chromone. Suppression of NF-κB activation led to inhibition of anti-apoptotic (Bcl-2, Bcl-xL, survivin, and cIAP-1), proliferative (cyclin D1 and COX-2), invasive (MMP-9 and ICAM-1), and angiogenic (VEGF) gene products and sensitization of tumor cells to cytokines. Thus, this study shows that modification of cysteine residues in IKK and p65 by 3-FC leads to inhibition of the NF-κB activation pathway, suppression of anti-apoptotic gene products, and potentiation of apoptosis in tumor cells.
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics.
authors: Vivek R
authors: VR
authors: Yadav
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics.
authors: Sahdeo
authors: S
authors: Prasad
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics.
authors: Subash C
authors: SC
authors: Gupta
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics.
authors: Bokyung
authors: B
authors: Sung
authors: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors: Sharangdhar S
authors: SS
authors: Phatak
authors: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors: Shuxing
authors: S
authors: Zhang
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics. Electronic address: aggarwal@mdanderson.org.
authors: Bharat B
authors: BB
authors: Aggarwal
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000378:metabolism / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics; D003545:Cysteine; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D059748:Proteolysis / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000737:chemistry* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D002867:Chromones; D051546:Cyclooxygenase 2; D003545:Cysteine; D004247:DNA; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C502480:formylchromone