title: A splicing variant of NME1 negatively regulates NF-κB signaling and inhibits cancer metastasis by interacting with IKKβ.
abstract: IKKβ functions as a principal upstream activator of the canonical NF-κB pathway by phosphorylating IκB, leading to its proteasomal degradation. Because IKKβ is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKβ-interacting molecule, NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its antimetastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKKβ. Exogenous expression of NME1L resulted in a potent decrease in TNFα-stimulated NF-κB activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF-κB. NME1L down-regulates IKKβ signaling by blocking IKKβ-mediated IκB degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in a metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent antimetastatic protein and may be a useful weapon in the fight against cancers.
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Dong-Joo
authors.initials: DJ
authors.lastname: You
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Cho Rong
authors.initials: CR
authors.lastname: Park
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Hyun Bok
authors.initials: HB
authors.lastname: Lee
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Moon
authors.affiliation: the National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: the Life Sciences Division, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Korea.
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.affiliation: the College of Pharmacy, Gachon University, Incheon 406-840, Korea, and.
authors.forename: Seong-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: the Transplantation Research Institute, Cancer Research Institute, Seoul National University, Yongun-dong, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.affiliation: From the Graduate School of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea, hjibio@korea.ac.kr.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D016328:NF-kappa B; D054778:NM23 Nucleoside Diphosphate Kinases; D009363:Neoplasm Proteins; D051550:I-kappa B Kinase; C517938:NME1 protein, human
keywords: Cancer; IKKbeta; Invasion; Metastasis; Migration; NF-kappaB; NME1L