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Abstract
Background: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.Methods: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.Results: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.Conclusions: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.
Highlights
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
ALPL expression was increased in PCa cells from metastatic sites
In men with PCa, tumour-derived ALPL correlated with epithelial-to-mesenchymal transition (EMT) markers, and high ALPL expression was associated with a significant reduction in disease-free survival
Summary
Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ARCaP, ARCaPE and ARCaPM human prostate cancer cells lines were purchased from Novicure Inc. All three cell lines were routinely maintained in MCaP medium C4-2B human prostate cancer cells were a kind gift from Prof. PC3 human prostate cancer cell line, obtained from American Type Culture Collection (ATCC, Teddington, UK), were routinely maintained in complete RPMI medium (Sigma-Aldrich, Gillingham, UK) containing 10% FBS and penicillin–streptomycin. All other prostate cancer cell lines were a kind gift from Dr Richard Bryant (University of Oxford, Oxford, UK). 2T3 mouse preosteoblast cells were obtained from ATCC and maintained in RPMI-1640 medium with 10% FBS and antibiotics, unless otherwise indicated. Periodic testing ensured the absence of mycoplasma contamination in all cell lines
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