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- Title
A Novel Role for Wnt/Ca<sup>2+</sup> Signaling in Actin Cytoskeleton Remodeling and Cell Motility in Prostate Cancer.
- Authors
Qin Wang; Symes, Andrew J.; Kane, Corrina A.; Freeman, Alex; Nariculam, Joseph; Munson, Philippa; Thrasivoulou, Christopher; Masters, John R. W.; Ahmed, Aamir
- Abstract
Wnt signaling is a critical regulatory pathway in development and disease. Very little is known about the mechanisms of Wnt signaling in prostate cancer, a leading cause of death in men. A quantitative analysis of the expression of Wnt5A protein in human tissue arrays, containing 600 prostate tissue cores, showed >50% increase in malignant compared to benign cores (p,0.0001). In a matched pair of prostate cancer and normal cell line, expression of Wnt5A protein was also increased. Calcium waves were induced in prostate cells in response to Wnt5A with a 3 fold increase in Flou-4 intensity. The activity of Ca2+/calmodulin dependent protein kinase (CaMKII), a transducer of the non-canonical Wnt/Ca2+ signaling, increased by 8 fold in cancer cells; no change was observed in β-catenin expression, known to activate the canonical Wnt/β-catenin pathway. Mining of publicly available human prostate cancer oligoarray datasets revealed that the expression of numerous genes (e.g., CCND1, CD44) under the control of β-catenin transcription is down-regulated. Confocal and quantitative electron microscopy showed that specific inhibition of CaMKII in cancer cells causes remodeling of the actin cytoskeleton, irregular wound edges and loose intercellular architecture and a 6 and 8 fold increase in the frequency and length of filopodia, respectively. Conversely, untreated normal prostate cells showed an irregular wound edge and loose intercellular architecture; incubation of normal prostate cells with recombinant Wnt5A protein induced actin remodeling with a regular wound edge and increased wound healing capacity. Live cell imaging showed that a functional consequence of CaMKII inhibition was 80% decrease in wound healing capacity and reduced cell motility in cancer cells. We propose that noncanonical Wnt/Ca2+ signaling via CaMKII acts as a novel regulator of structural plasticity and cell motility in prostate cancer.
- Publication
PLoS ONE, 2010, Vol 5, Issue 5, p1
- ISSN
1932-6203
- Publication type
Academic Journal
- DOI
10.1371/journal.pone.0010456