Molecular Signaling Pathways Mediating Osteoclastogenesis Induced by Prostate Cancer Cells

BMC Cancer

Svetlana V Komarova²  Shahrzad Rafiei¹ 

[1]Shriners Hospital for Children-Canada, 1529 Cedar Avenue, room-300, Montreal, Quebec H3G IA6, Canada

[2]Faculty of Dentistry, McGill University, 3640 University Street, Montreal, Quebec H3A 0C7, Canada

关键词: ERK1/2;    NFATc1;    Calcium signaling;    Osteoclast;    Bone metastasis;    Prostate cancer;   

Others  :  859187
DOI  :  10.1186/1471-2407-13-605

 received in 2013-10-07, accepted in 2013-12-16,  发布年份 2013

【 摘 要 】

Background

Advanced prostate cancer commonly metastasizes to bone leading to osteoblastic and osteolytic lesions. Although an osteolytic component governed by activation of bone resorbing osteoclasts is prominent in prostate cancer metastasis, the molecular mechanisms of prostate cancer-induced osteoclastogenesis are not well-understood.

Methods

We studied the effect of soluble mediators released from human prostate carcinoma cells on osteoclast formation from mouse bone marrow and RAW 264.7 monocytes.

Results

Soluble factors released from human prostate carcinoma cells significantly increased viability of naïve bone marrow monocytes, as well as osteoclastogenesis from precursors primed with receptor activator of nuclear factor κ-B ligand (RANKL). The prostate cancer-induced osteoclastogenesis was not mediated by RANKL as it was not inhibited by osteoprotegerin (OPG). However inhibition of TGFβ receptor I (TβRI), or macrophage-colony stimulating factor (MCSF) resulted in attenuation of prostate cancer-induced osteoclastogenesis. We characterized the signaling pathways induced in osteoclast precursors by soluble mediators released from human prostate carcinoma cells. Prostate cancer factors increased basal calcium levels and calcium fluctuations, induced nuclear localization of nuclear factor of activated t-cells (NFAT)c1, and activated prolonged phosphorylation of ERK1/2 in RANKL-primed osteoclast precursors. Inhibition of calcium signaling, NFATc1 activation, and ERK1/2 phosphorylation significantly reduced the ability of prostate cancer mediators to stimulate osteoclastogenesis.

Conclusions

This study reveals the molecular mechanisms underlying the direct osteoclastogenic effect of prostate cancer derived factors, which may be beneficial in developing novel osteoclast-targeting therapeutic approaches.

【 授权许可】

   
2013 Rafiei and Komarova; licensee BioMed Central Ltd.

【 图 表 】

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