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The effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway
Author(s) -
Honda Yohji,
Takahashi Shoichi,
Zhang Yizhou,
Ono Atsushi,
Murakami Eisuke,
Shi Niu,
Kawaoka Tomokazu,
Miki Daiki,
Tsuge Masataka,
Hiraga Nobuhiko,
Abe Hiromi,
Ochi Hidenori,
Imamura Michio,
Aikata Hiroshi,
Chayama Kazuaki
Publication year - 2015
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12715
Subject(s) - rhoa , mevalonate pathway , cancer research , medicine , flow cytometry , cell growth , bisphosphonate , hepatocellular carcinoma , apoptosis , zoledronic acid , mapk/erk pathway , immunohistochemistry , viability assay , metastasis , cell , pathology , cancer , kinase , signal transduction , immunology , chemistry , biology , microbiology and biotechnology , biochemistry , osteoporosis , reductase , enzyme
Background and Aim Zoledronic acid ( ZOL ) is a nitrogen‐containing bisphosphonate and is used to reduce cancer‐induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects. Methods Cell viability assay, scratch assay, immunohistochemistry, W estern blotting, and flow cytometry analysis were performed using H uh7 and H ep G 2 cells treated with and without ZOL . Results ZOL reduced cell growth in a dose‐dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of R as and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen‐activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells. Conclusions Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.