title: Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma.
abstract: A well-characterized murine osteosarcoma model for metastasis and invasion was used in this study to determine the role of AP-1 in the progression of this disease. We analyzed K12 and K7M2 cells, two clonally related murine osteosarcoma cell lines that have been characterized as low metastatic or high metastatic, respectively, for AP-1 components and activity. AP-1 DNA binding was similar between the two cell lines; however AP-1 transcriptional activity was enhanced by 3- to 5-fold in K7M2 cells relative to that in K12 cells. The AP-1 complexes in K12 and K7M2 cells was composed primarily of cJun, JunD, FosB, Fra1, and Fra2, with the contribution of individual components in the complex varying between the two cell lines. In addition, an increase in phosphorylated cJun, JNK activity, and phosphorylated ERK1/2 was associated with the more metastatic osteosarcoma phenotype. The significance of AP-1 activation was confirmed by conditional expression of TAM67, a dominant negative mutant of cJun. Under conditions where TAM67 inhibited AP-1 activity in K7M2 cells, migration and invasion potential was significantly blocked. Tam67 expression in aggressive osteosarcoma cells decreased long-term in vivo experimental metastasis and increased survival of mice. This study shows that differences in metastatic activity can be due to AP-1 activation. The inhibition of AP-1 activity may serve as a therapeutic tool in the management of osteosarcoma.
authors.affiliation: Cell and Cancer Biology Department, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Virna D
authors.initials: VD
authors.lastname: Leaner
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Chick
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.forename: Ilona
authors.initials: I
authors.lastname: Linniola
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Mendoza
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D018808:Transcription Factor AP-1