title: β-Caryophyllene oxide potentiates TNFα-induced apoptosis and inhibits invasion through down-modulation of NF-κB-regulated gene products.
abstract: We have recently reported that β-caryophyllene oxide (CPO) can induce apoptosis, suppress tumor growth, and inhibit metastasis through the suppression of signal transducer and activator of transcription 3, PI3K/AKT/mTOR/S6K1 signaling cascades and ROS-mediated MAPKs activation. In the present study, we found that CPO potentiated the apoptosis induced by tumor necrosis factor α (TNFα) and chemotherapeutic agents, suppressed TNFα-induced tumor cell invasion, all of which are known to require NF-κB activation. We found that TNFα stimulated the expression of gene products involved in anti-apoptosis (IAP1, IAP2, Bcl-2, Bcl-xL, and survivin), proliferation (COX-2, cyclin D1, and c-Myc), invasion (MMP 9 and ICAM-1), and angiogenesis (VEGF) and that CPO treatment suppressed their expression. Because these gene products are also regulated by proinflammatory transcription factor NF-κB, we postulated that CPO may mediate its effects by modulating the NF-κB pathway. We found that CPO blocked both inducible and constitutive NF-κB activation in a wide variety of tumor cells. CPO was also found to inhibit the TNFα-induced degradation of IκBα through the inhibition of activation of IκBα kinase and p65 nuclear translocation and phosphorylation. Interestingly, CPO failed to potentiate the apoptotic effect induced by TNFα in p65 (-/-) cells as compared to the wild-type. Thus, overall, our results indicate that the inhibition of NF-κB is one of major mechanisms by which CPO enhances TNFα-induced apoptosis and suppresses invasion.
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong Dongdaemungu, Seoul, 130-701, Republic of Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.forename: Somi K
authors.initials: SK
authors.lastname: Cho
authors.forename: Ki-Dong
authors.initials: KD
authors.lastname: Kim
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Chung
authors.forename: Hyeung-Jin
authors.initials: HJ
authors.lastname: Jang
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C515179:caryophyllene oxide