Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer.
Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.
Ichiki
K
K
Department of Pathogenic Biochemistry, Institute ot Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Mitani
N
N
Doki
Y
Y
Hara
H
H
Misaki
T
T
Saiki
I
I
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007700:Kinetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008479:Mediastinal Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; C524899:Plaur protein, mouse; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; D014568:Urokinase-Type Plasminogen Activator; D003474:Curcumin; D002945:Cisplatin