Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells

Leclerc, J. C.; Garandeau, David; Pandiani, Charlotte; Gaudel, Céline; Bille, Karine; Nottet, Nicolas; Garcia, Virginie; Colosetti, Pascal; Pagnotta, Sophie; Bahadoran, Philippe; Tondeur, G; Mograbi, Baharia; Dalle, S.; Caramel, Julie; Levade, Thierry; Ballotti, Robert; Andrieu‐Abadie, Nathalie; Bertolotto, Corine

doi:10.1038/s41388-018-0500-0

Cited by 38 publications

(36 citation statements)

References 63 publications

(15 reference statements)

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“…This makes sense, as elevated protein synthesis is necessary for cell proliferation, which is also promoted by MITF, but can potentially also lead to feedback regulation in that MITF, particularly the isoforms containing the 1B1b exon, can be retained in the cytoplasm in response to phosphorylation by activated mTORC1 (Martina and Puertollano 2013;Ngeow et al 2018) (for more details see below). Recent evidence also indicates that MITF can control the expression of the lysosomal acid ceramidase ASAH1 that controls sphingolipid metabolism (Leclerc et al 2019). Significantly ectopic expression of ASAH1 could rescue the cell cycle defects associated with MITF depletion, consistent with a role for ASAH1 in promoting melanoma proliferation (Realini et al 2016).…”

Section: Mitf Target Genes and Biological Rolementioning

confidence: 91%

MITF—the first 25 years

2019

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Section: Mitf Target Genes and Biological Rolementioning

confidence: 91%

MITF—the first 25 years

2019

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“…AC is part of a family of lipid hydrolases that cleave ceramide to form sphingosine, which can be subsequently phosphorylated to produce S1P. AC is upregulated in several cancers (18)(19)(20)(21). We recently established that it is the highest expressed and most upregulated ceramidase in AML and mediates survival of AML cells (22).…”

Section: Introductionmentioning

confidence: 99%

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

Pearson

Tan

Sharma

et al. 2020

Molecular Cancer Research

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Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 μmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative MCL-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or MCL-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models. Implications: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development.

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“…1,2 Several reports sustain the involvement of ceramidases in the development of malignancies and in the failure of their treatment. Some examples include the role of acid ceramidase (AC) in melanoma, [3][4][5][6] prostate cancer 7,8 and acute myeloid leukemia, 9,10 the implication of neutral ceramidase (NC) in colorectal cancer 11 and the contribution of alkaline ceramidase 3 (ACER3) to hepatocellular carcinoma 12 and acute myeloid leukemia. 13 On the other hand, mutations in the genes encoding for AC 14 and ACER3 15 have been discovered to cause rare inherited diseases.…”

Section: Introductionmentioning

confidence: 99%