Acid ceramidase 1 expression correlates with a better prognosis in ER-positive breast cancer

Ruckhäberle, Eugen; Holtrich, Uwe; Engels, Knut; Hanker, Lars; Gätje, Regine; Metzler, Dirk; Karn, Thomas; Kaufmann, M.; Rody, Achim

doi:10.3109/13697130902939913

Cited by 41 publications

(11 citation statements)

References 52 publications

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“…4D). In agreement with our findings, ASAH1 expression was shown to positively correlate with ER status in breast cancer tumors (50) and ER-positive tumors display higher ASAH1 expression (69), supporting a role for ER in the transcriptional regulation of the ASAH1 gene.…”

Section: Discussionsupporting

confidence: 89%

“…1A). Because aberrant ASAH1 expression has been reported in cancer cells (46,49,50), we focused on the effect of genistein on the transcription of this ceramidase isoform. We carried out experiments to assess the kinetics of the ASAH1 transcriptional response to genistein by treating cells for 6, 12, and 24 h. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because Cer hydrolysis is the major pathway for SPH generation (45), ASAH1 plays a key role in regulating cellular homeostasis by controlling the Cer/SPH/S1P balance within the cell. In addition, the aberrant expression of ASAH1 in various human cancers (46 -49), including breast cancer (50), prompted the emergence of this enzyme as a potential target for chemotherapy (48,51,52). Inhibitors of ASAH1 such as B13 and LCL464 were shown to cause Cer accumulation and prevent tumor growth (51,53).…”

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confidence: 99%

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Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

Lucki

Sewer

2011

Journal of Biological Chemistry

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Sphingolipid metabolites, such as ceramide (Cer), sphingosine (SPH), and sphingosine 1-phosphate (S1P), contribute to multiple aspects of carcinogenesis including cell proliferation, migration, angiogenesis, and tumor resistance. The cellular balance between Cer and S1P levels, for example, is an important determinant of cell fate, with the former inducing apoptosis and the later mitogenesis. Acid ceramidase (ASAH1) plays a pivotal role in regulating the intracellular concentration of these two metabolites by hydrolyzing Cer into SPH, which is rapidly phosphorylated to form S1P. Genistein is a phytoestrogen isoflavone that exerts agonist and antagonist effects on the proliferation of estrogen-dependent MCF-7 cells in a dose-dependent manner, primarily as a ligand for estrogen receptors. Genistein can also activate signaling through GPR30, a G-protein-coupled cell surface receptor. Based on the relationship between bioactive sphingolipids and tumorigenesis, we sought to determine the effect of genistein on ASAH1 transcription in MCF-7 breast cancer cells. We show herein that nanomolar concentrations of genistein induce ASAH1 transcription through a GPR30-dependent, pertussis toxin-sensitive pathway that requires the activation of c-Src and extracellular signal regulated kinase 1/2 (ERK1/2). Activation of this pathway promotes histone acetylation and recruitment of phospho-estrogen receptor ␣ and specificity protein-1 to the ASAH1 promoter, ultimately culminating in increased ceramidase activity. Finally, we show that genistein stimulates cyclin B2 expression and cell proliferation in an ASAH1-dependent manner. Collectively, these data identify a mechanism through which genistein promotes sphingolipid metabolism and support a role for ASAH1 in breast cancer cell growth.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

Lucki

Sewer

2011

Journal of Biological Chemistry

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“…The ASAH1-SPHK1-S1P pathway also promotes prostate cancer cell invasiveness through up-regulation of the matrix protease Cathepsin B [178]. Even though ASAH1 and SPHK1 are sequential enzymes of the same pathway and have been functionally linked as described above, high ASAH1 expression has been associated with a positive outcome in epithelial ovarian and estrogen receptor positive breast cancers [179,180]. The opposite was suggested to be the case in prostate cancer, although numbers were not sufficient for robust statistical analysis [178].…”

Section: Studies On Individual Enzymes and Sphingolipid Metabolitementioning

confidence: 99%

Re-Configuration of Sphingolipid Metabolism by Oncogenic Transformation

2014

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The sphingolipids are one of the major lipid families in eukaryotes, incorporating a diverse array of structural variants that exert a powerful influence over cell fate and physiology. Increased expression of sphingosine kinase 1 (SPHK1), which catalyses the synthesis of the pro-survival, pro-angiogenic metabolite sphingosine 1-phosphate (S1P), is well established as a hallmark of multiple cancers. Metabolic alterations that reduce levels of the pro-apoptotic lipid ceramide, particularly its glucosylation by glucosylceramide synthase (GCS), have frequently been associated with cancer drug resistance. However, the simple notion that the balance between ceramide and S1P, often referred to as the sphingolipid rheostat, dictates cell survival contrasts with recent studies showing that highly potent and selective SPHK1 inhibitors do not affect cancer cell proliferation or survival, and studies demonstrating higher ceramide levels in some metastatic cancers. Recent reports have implicated other sphingolipid metabolic enzymes such as acid sphingomyelinase (ASM) more strongly in cancer pathogenesis, and highlight lysosomal sphingolipid metabolism as a possible weak point for therapeutic targeting in cancer. This review describes the evidence implicating different sphingolipid metabolic enzymes and their products in cancer pathogenesis, and suggests how newer systems-level approaches may improve our overall understanding of how oncogenic transformation reconfigures sphingolipid metabolism.

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“…Combination of Akt and aCDase inhibitors synergistically inhibit cell viability/proliferation more effectively than single-agent treatments [37]. Moreover, aCDase has been described as an estrogen-dependent enzyme that might provide prognostic information in ER-positive breast cancers [38]. In another study, aCDase was downregulated in response to tamoxifen, suggesting that aCDase plays a crucial role in mediating the anti-estrogen activity of tamoxifen in treatment of breast cancer [39].…”

Section: Acid Ceramidasementioning

confidence: 99%

Small Molecule Inhibitors of Ceramidases

Saied

2014

Cell Physiol Biochem

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The equilibrium between the pro-apoptotic ceramide and pro-vital sphingosine-1-phosphate is considered to be decisive for cell death or survival. The different ceramidases thus play key roles in cell fate and might offer attractive targets for pharmacological intervention. Although until recently only moderately active inhibitors have been described, first in vivo experiments suggest activity against cancer cell survival and multi-drug resistance. Here, we provide a brief overview on the different ceramidases, and we will review the known inhibitors and current strategies for further inhibitor development.

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Acid ceramidase 1 expression correlates with a better prognosis in ER-positive breast cancer

Abstract: ASAH1 is an estrogen-dependent member of the sphingolipid metabolism, which might provide further prognostic information in ER-positive breast cancers.

Cited by 41 publications

References 52 publications

Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

Genistein Stimulates MCF-7 Breast Cancer Cell Growth by Inducing Acid Ceramidase (ASAH1) Gene Expression

Re-Configuration of Sphingolipid Metabolism by Oncogenic Transformation

Small Molecule Inhibitors of Ceramidases

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