Acid ceramidase as a therapeutic target in metastatic prostate cancer

被引：61

作者：

Camacho, Luz ^{[1
]}

Meca-Cortes, Oscar ^{[2
]}

Luis Abad, Jose ^{[1
]}

Garcia, Simon ^{[2
]}

Rubio, Nuria ^{[3
]}

Diaz, Alba ^{[4
,5
]}

Celia-Terrassa, Toni ^{[2
]}

Cingolani, Francesca ^{[1
]}

Bermudo, Raquel ^{[4
,5
,6
]}

Fernandez, Pedro L. ^{[4
,5
,6
,7
,8
]}

Blanco, Jeronimo ^{[3
]}

Delgado, Antonio ^{[1
,9
]}

Casas, Josefina ^{[1
]}

Fabrias, Gemma ^{[4
,5
]}

Thomson, Timothy M. ^{[2
]}

机构：

[1] Natl Res Council IQAC CSIC, Inst Adv Chem Catalonia, Dept Biomed Chem, Res Unit Bioact Mol RUBAM, Barcelona, Spain

[2] Natl Res Council IBMB CSIC, Mol Biol Inst Barcelona, Dept Cell Biol, Barcelona, Spain

[3] CIBER BBN, Natl Res Council ICCC CSIC, Cardiovasc Res Ctr, Barcelona, Spain

[4] Hosp Clin Barcelona, Tumor Bank, Barcelona, Spain

[5] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Biobank, Barcelona, Spain

[6] Inst Invest Biomed August Pi & Suner IDIBAPS, Human & Expt Funct Oncomorphol Grp, Barcelona, Spain

[7] Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain

[8] Univ Barcelona, Fac Pharm, Sch Med, Barcelona, Spain

[9] Univ Barcelona, Fac Pharm, Unit Med Chem, Barcelona, Spain

来源：

JOURNAL OF LIPID RESEARCH | 2013年 / 54卷 / 05期

关键词：

ceramide; metastasis; inhibitors; SPHINGOLIPID METABOLISM; SPHINGOMYELIN SYNTHASE; TUMOR-GROWTH; STEM-CELLS; INHIBITORS; RESISTANCE; SIGNATURE; ANALOGS; B13; ACTIVATION;

D O I：

10.1194/jlr.M032375

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1207 / 1220

页数：14

共 57 条

[1] Synthesis and bioevaluation of ω-N-amino analogs of B13 [J].

Bai, Aiping ;

Szulc, Zdzislaw M. ;

Bielawski, Jacek ;

Mayroo, Nalini ;

Liu, Xiang ;

Norris, James ;

Hannun, Yusuf A. ;

Bielawska, Alicja .

BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (05) :1840-1848

[2] Alteration of Ceramide 1-O-Functionalization as a Promising Approach for Cancer Therapy [J].

Ballereau, Stephanie ;

Levade, Thierry ;

Genisson, Yves ;

Andrieu-Abadie, Nathalie .

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2012, 12 (04) :316-328

[3] Synthesis of a novel ceramide analogue and its use in a high-throughput fluorogenic assay for ceramidases [J].

Bedia, Carmen ;

Casas, Josefina ;

Garcia, Virginie ;

Levade, Thierry ;

Fabrias, Gemma .

CHEMBIOCHEM, 2007, 8 (06) :642-648

[4] Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine [J].

Bedia, Carmen ;

Casas, Josefina ;

Andrieu-Abadie, Nathalie ;

Fabrias, Gemma ;

Levade, Thierry .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (32) :28200-28209

[5] A simple fluorogenic method for determination of acid ceramidase activity and diagnosis of Farber disease [J].

Bedia, Carmen ;

Camacho, Luz ;

Luis Abad, Jose ;

Fabrias, Gemma ;

Levade, Thierry .

JOURNAL OF LIPID RESEARCH, 2010, 51 (12) :3542-3547

[6] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[7] Ceramide in Stem Cell Differentiation and Embryo Development: Novel Functions of a Topological Cell-Signaling Lipid and the Concept of Ceramide Compartments [J].

Bieberich, Erhard .

JOURNAL OF LIPIDS, 2011, 2011

[8] Novel analogs of D-e-MAPP and B13.: Part 2:: Signature effects on bioactive sphingolipids [J].

Bielawska, Alicja ;

Bielawski, Jacek ;

Szulc, Zdzislaw M. ;

Mayroo, Nalini ;

Liu, Xiang ;

Bai, AiPing ;

Elojeimy, Saeed ;

Rembiesa, Barbara ;

Pierce, Jason ;

Norris, James S. ;

Hannun, Yusuf A. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2008, 16 (02) :1032-1045

[9] Ceramide kinase: The first decade [J].

Bornancin, Frederic .

CELLULAR SIGNALLING, 2011, 23 (06) :999-1008

[10] Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases [J].

Canals, Daniel ;

Perry, David M. ;

Jenkins, Russell W. ;

Hannun, Yusuf A. .

BRITISH JOURNAL OF PHARMACOLOGY, 2011, 163 (04) :694-712

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