期刊
DIFFERENTIATION
卷 78, 期 4, 页码 213-222出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.diff.2009.07.008
关键词
GDF-15; Osteoclast; LNCaP; RAW264.7; Prostate cancer
资金
- Czech Science Foundation [301/06/0036, 301/09/1115, 204/08/H054, 204/07/0834, 310/07/0961]
- Ministry of Education, Youth and Sports of the Czech Republic [MSM0021622415]
- Academy of Sciences of the Czech Republic [AV0Z50040507, AV0Z50040702]
- Ministry of Health of the Czech Republic [IGA9875-4]
Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiationfactor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D-3-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NF kappa B by delayed degradation of I kappa B. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases. (C) 2009 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.
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