Bone Morphogenetic Protein-9 Induces Apoptosis in Prostate Cancer Cells, the Role of Prostate Apoptosis Response-4

Abstract

Bone morphogenetic proteins (BMP) have been implicated in the development of bone metastases in prostate cancer. In this study, we investigated the role which BMP-9 played in prostate cancer and found that the expression of BMP-9 was decreased or absent in prostate cancer, particularly in the foci of higher grade disease. We further investigated the influence of BMP-9 on the biological behaviors of prostate cancer cells. The forced overexpression of BMP-9 prevented the in vitro growth, cell-matrix adhesion, invasion, and migration of prostate cancer cells. We also elucidated that BMP-9 induced apoptosis in PC-3 cells through the up-regulation of prostate apoptosis response-4. Among the receptors which have been implicated in the signaling of BMP-9, BMPR-IB and BMPR-II have also been implicated in the development and progression of prostate cancer. Knockdown of BMPR-IB or BMPR-II using respective hammerhead ribozyme transgenes could promote cell growth in vitro. We also found that BMPR-II is indispensable for the Smad-dependent signal transduction by BMP-9 in PC-3 cells, in which Smad-1 was phosphorylated and translocated from the cytoplasm into the nuclei. Taken together, BMP-9 inhibits the growth of prostate cancer cells due to the induced apoptosis, which is related to an up-regulation of prostate apoptosis response-4 through a Smad-dependent pathway. BMP-9 could also prevent the migration and invasiveness of prostate cancer. This suggests that BMP-9 may function as a tumor suppressor and apoptosis regulator in prostate cancer.