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: Luz Camacho, Oscar Meca-Cortés, José Luis Abad, Simón García, Nuria Rubio, Alba Díaz, Toni Celià-Terrassa, Francesca Cingolani, Raquel Bermudo, Pedro L Fernández, Jerónimo Blanco, Antonio Delgado, Josefina Casas, Gemma Fabriàs, Timothy M Thomson
• Journal: Journal of lipid research (J Lipid Res) Vol. 54 Issue 5 Pg. 1207-20 (May 2013) ISSN: 1539-7262 [Electronic] United States
• PMID: 23423838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Lysophospholipids
• sphingosine 1-phosphate
• Acid Ceramidase
• Sphingosine

Topics

• Acid Ceramidase (antagonists & inhibitors, genetics, metabolism)
• Apoptosis (genetics)
• Cell Line, Tumor
• Ceramides (metabolism)
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Lysophospholipids (metabolism)
• Male
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Prostatic Neoplasms (genetics, pathology, therapy)
• Sphingosine (analogs & derivatives, metabolism)