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.