p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient expression of the Wnt inhibitor Dickkopf-1

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-12, Vol.70 (23), p.9916-9926
• Main Authors: Hall, Christopher L, Zhang, Honglai, Baile, Shobun, Ljungman, Mats, Kuhstoss, Stuart, Keller, Evan T
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; G1 Phase; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Nude; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Oligonucleotide Array Sequence Analysis; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Transplantation, Heterologous; Tumor Burden; Wnt Proteins - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0440

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.