TY - JOUR
T1 - Acid ceramidase as a therapeutic target in metastatic prostate cancer
AU - Camacho, Luz
AU - Meca-Cortes, Oscar
AU - Luis Abad, Jose
AU - Garcia, Simon
AU - Rubio, Nuria
AU - Diaz, Alba
AU - Celia-Terrassa, Toni
AU - Cingolani, Francesca
AU - Bermudo, Raquel
AU - Fernandez, Pedro L.
AU - Blanco, Jeronimo
AU - Delgado, Antonio
AU - Casas, Josefina
AU - Fabrias, Gemma
AU - Thomson, Timothy M.
PY - 2013/5
Y1 - 2013/5
N2 - Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confirm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specific AC inhibitors could act by counteracting critical growth properties of these highly aggressive tumor cells.-Camacho, L., O. MecaCortes, J. L. Abad, S. Garcia, N. Rubio, A. Diaz, T. Celia-Terrassa, F. Cingolani, R. Bermudo, P. L. Fernandez, J. Blanco, A. Delgado, J. Casas, G. Fabrias, and T. M. Thomson. Acid ceramidase as a therapeutic target in metastatic prostate cancer. J. Lipid Res. 2013. 54: 1207-1220.
AB - Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confirm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specific AC inhibitors could act by counteracting critical growth properties of these highly aggressive tumor cells.-Camacho, L., O. MecaCortes, J. L. Abad, S. Garcia, N. Rubio, A. Diaz, T. Celia-Terrassa, F. Cingolani, R. Bermudo, P. L. Fernandez, J. Blanco, A. Delgado, J. Casas, G. Fabrias, and T. M. Thomson. Acid ceramidase as a therapeutic target in metastatic prostate cancer. J. Lipid Res. 2013. 54: 1207-1220.
KW - ceramide
KW - metastasis
KW - inhibitors
KW - SPHINGOLIPID METABOLISM
KW - SPHINGOMYELIN SYNTHASE
KW - TUMOR-GROWTH
KW - STEM-CELLS
KW - INHIBITORS
KW - RESISTANCE
KW - SIGNATURE
KW - ANALOGS
KW - B13
KW - ACTIVATION
U2 - 10.1194/jlr.M032375
DO - 10.1194/jlr.M032375
M3 - Article
SN - 0022-2275
VL - 54
SP - 1207
EP - 1220
JO - J. Lipid Research
JF - J. Lipid Research
IS - 5
ER -
