title: Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-κB activity.
abstract: Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-κB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-κB signaling.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mitsuhashi
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Atsuro
authors.initials: A
authors.lastname: Saijo
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C571158:Dll4-Fc protein; D016328:NF-kappa B; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins