Osteoblasts-derived BMP-2 enhances the motility of prostate cancer cells via activation of integrins.
BACKGROUND
Bone metastases are common complications of prostate cancer cells. The bone morphogenetic protein-2 (BMP-2) is constitutively secreted by osteoblasts and plays a key role in bone formation. Integrins are the major adhesive molecules in mammalian cells, and has been associated with cancer cells metastasis to bone. The aim of this study was to investigate whether osteoblast-derived BMP-2 is associated with prostate cancer metastasis.


METHODS
Cancer cells migration activity was examined using the Transwell assay. The ERK and AKT phosphorylation was examined by using Western blot method. The siRNA was used to inhibit the expression of BMP-2. The cell surface expression of integrins was examined by using flow cytometry. A transient transfection protocol was used to examine NF-kappaB activity.


RESULTS
We found that osteoblast conditioned medium (OBCM) increased the migration and cell surface expression of beta1 or beta 3 integrin in human prostate cancer cells. beta1 or beta 3 integrin monoclonal antibodies or siRNA against beta1 or beta 3 integrin inhibited the OBCM-induced increase the migration of prostate cancer cells. BMP-2 siRNA specifically reduced the OBCM-induced migration and integrins upregulation. BMP-2 siRNA also suppressed the OBCM-induced ERK, AKT and NF-kappaB activation.


CONCLUSIONS
This study suggest that the osteoblast-derived BMP-2 act through Akt and ERK, which in turn activates IKK alpha/beta and NF-kappaB, resulting in the activations of beta1 and beta 3 integrins and contributing the migration of prostate cancer cells.
Lai
Tzu-Hsiu
TH
Department of Pharmacology, China Medical University, Taichung, Taiwan.
Fong
Yi-Chin
YC
Fu
Wen-Mei
WM
Yang
Rong-Sen
RS
Tang
Chih-Hsin
CH
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D019012:Integrin beta1; D039661:Integrin beta3; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases