Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells.
We found that bone morphogenetic protein (BMP) 7, a member of the BMP family, was strikingly up-regulated during the development of primary prostatic adenocarcinoma in the conditional Pten deletion mouse model. To determine the relevance of this finding to human prostate cancer, we examined the expression of BMPs and BMP receptors (BMPR) as well as the responsiveness to recombinant human BMP7 in a series of human prostate tumor cell lines. All prostatic cell lines tested expressed variable levels of BMP2, BMP4, and BMP7 and at least two of each type I and II BMPRs. In all cases, BMP7 induced Smad phosphorylation in a dose-dependent manner, with Smad5 activation clearly demonstrable. However, the biological responses to BMP7 were cell type specific. BPH-1, a cell line representing benign prostatic epithelial hyperplasia, was growth arrested at G1. In the bone metastasis-derived PC-3 prostate cancer cells, BMP7 induced epithelial-mesenchymal transdifferentiation with classic changes in morphology, motility, invasiveness, and molecular markers. Finally, BMP7 inhibited serum starvation-induced apoptosis in the LNCaP prostate cancer cell line and more remarkably in its bone metastatic variant C4-2B line. Each of the cell lines influenced by BMP7 was also responsive to BMP2 in a corresponding manner. The antiapoptotic activity of BMP7 in the LNCaP and C4-2B cell lines was not associated with a significant alteration in the levels of the proapoptotic protein Bax or the antiapoptotic proteins Bcl-2, Bcl-xl, and X-linked inhibitor of apoptosis. However, in C4-2B cells but not in LNCaP cells, a starvation-induced decrease in the level of survivin was counteracted by BMP7. Taken together, these findings suggest that BMPs are able to modulate the biological behavior of prostate tumor cells in diverse and cell type-specific manner and point to certain mechanisms by which these secreted signaling molecules may contribute to prostate cancer growth and metastasis.
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Shangxin
S
Yang
Chen
C
Zhong
Baruch
B
Frenkel
A Hari
AH
Reddi
Pradip
P
Roy-Burman
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta