Pitavastatin inactivates NF-kappaB and decreases IL-6 production through Rho kinase pathway in MCF-7 cells.
The aim of the present study was to provide new mechanistic insight into the effect of pitavastatin at low dose on NF-kappaB activated by TNF-alpha in the human breast cancer cell line (MCF-7). We found that treatment of MCF-7 with 1 microM pitavastatin inhibited the proliferation and suppressed the nuclear expression of NF-kappaB p65 induced by TNF-alpha with Western blotting. Furthermore, EMSA showed that pitavastatin significantly reduced the DNA binding activity of NF-kappaB induced by TNF-alpha. Subsequently, luciferase assay revealed that pitavastatin (1 microM) inhibited the transcriptional activity of the NF-kappaB promoter, which was clearly related to the HMG-CoA reductase activity because addition of mevalonic acid (MEV) could elevate the NF-kappaB activity. Moreover, the Rho kinase inhibitor Y27632 abolished the effect of pitavastatin on NF-kappaB activity. Finally, the addition of TNF-alpha significantly increased IL-6 protein production, which was suppressed by the addition of pitavastatin. These results suggest that pitavastatin at low dose (1 microM) inhibits NF-kappaB activation and decreases IL-6 production induced by TNF-alpha. It is dependent on Rho kinase pathway in human breast cancer cells.
Wang
Juyong
J
Department of Tumor, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China. wangjuyong1@126.com
Kitajima
Isao
I
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases; D000093242:Interleukin-6 Inhibitors
D004273:DNA, Neoplasm; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D054460:rho-Associated Kinases; D000093242:Interleukin-6 Inhibitors; C108475:pitavastatin