title: Acid ceramidase as a therapeutic target in metastatic prostate cancer.
abstract: 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.
authors: Department of Biomedicinal Chemistry, Research Unit on Bioactive Molecules (RUBAM), Institute for Advanced Chemistry of Catalonia, National Research Council (IQAC-CSIC), Barcelona, Spain.
authors: Luz
authors: L
authors: Camacho
authors: Oscar
authors: O
authors: Meca-Cortés
authors: José Luis
authors: JL
authors: Abad
authors: Simón
authors: S
authors: García
authors: Nuria
authors: N
authors: Rubio
authors: Alba
authors: A
authors: Díaz
authors: Toni
authors: T
authors: Celià-Terrassa
authors: Francesca
authors: F
authors: Cingolani
authors: Raquel
authors: R
authors: Bermudo
authors: Pedro L
authors: PL
authors: Fernández
authors: Jerónimo
authors: J
authors: Blanco
authors: Antonio
authors: A
authors: Delgado
authors: Josefina
authors: J
authors: Casas
authors: Gemma
authors: G
authors: Fabriàs
authors: Timothy M
authors: TM
authors: Thomson
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D055573:Acid Ceramidase; D013110:Sphingosine