Abstract
Osteoblastic bone metastases are the most common metastases produced by human prostate cancers (PCa). Deregulated activity of Wnt growth factors resulting from overexpression of the Wnt inhibitor Dickkopf-1 (DKK-1) is known to contribute to formation of the osteoblastic component of PCa skeletal bone metastases. In this study, we report that DKK-1 knockdown in osteolytic human PCa cells unexpectedly delays the development of both soft tissue and osseous lesions. PCa cells deficient in DKK-1 expression did not increase canonical Wnt signaling in target osteoblast cell lines; however, DKK-1 knockdown PCa cells exhibited increased expression of the CDK inhibitor p21(CIP1/WAF1) and a 32% increase in G(1) arrest compared with control cells. Ablating p21(CIP1/WAF1) in PCa cells deficient in DKK-1 was sufficient to rescue tumor growth. Collectively, our findings demonstrate that DKK-1 overexpression supports tumor growth in part by restricting expression of p21(CIP1/WAF1) through a mechanism independent of canonical Wnt signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Western
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / secondary
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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G1 Phase
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Male
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Mice
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Mice, Nude
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism*
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Neoplasms, Experimental / pathology
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Oligonucleotide Array Sequence Analysis
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Transplantation, Heterologous
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Tumor Burden
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Wnt Proteins / metabolism
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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DKK1 protein, human
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Intercellular Signaling Peptides and Proteins
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Wnt Proteins