Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone

• Published in: PloS one 2013-04, Vol.8 (4), p.e60983
• Main Authors: Jin, Renjie, Sterling, Julie A, Edwards, James R, DeGraff, David J, Lee, Changki, Park, Serk In, Matusik, Robert J
• Format: Article
• Language: English
• Subjects: Activation; Angiogenesis; Animals; B cells; Biocompatibility; Biology; Biomedical materials; Bone cancer; Bone growth; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Breast cancer; Cancer; Cancer cells; Cancer metastasis; Cancer research; Cell Line, Tumor; Cell migration; Cell Proliferation; Cell Transformation, Neoplastic; Conditioning; Cytokines; Deactivation; Development and progression; Down-Regulation; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Genes; Humans; I-kappa B Kinase - deficiency; I-kappa B Kinase - genetics; Inactivation; Lesions; Ligands; Male; Medicine; Metabolism; Metastases; Metastasis; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF-κB protein; Osteoblasts; Osteoclastogenesis; Osteoclasts; Osteoclasts - pathology; Osteolysis; Parathyroid hormone-related protein; Patients; Prostate cancer; Prostatic Neoplasms - pathology; Signal Transduction; Signaling; Studies; Surgery; TRANCE protein; Tumor Microenvironment; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060983

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.