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Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression.Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis.ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival.Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.

Original publication

DOI

10.1038/bjc.2016.402

Type

Journal article

Journal

British Journal of Cancer

Publication Date

01/2017

Volume

116

Pages

227 - 236

Addresses

Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.

Keywords

Cells, Cultured, Animals, Humans, Mice, Prostatic Neoplasms, Neoplasm Metastasis, Disease Progression, Alkaline Phosphatase, Disease-Free Survival, Cell Death, Cell Proliferation, Cell Movement, Male, HEK293 Cells, Epithelial-Mesenchymal Transition