DDRE-06. TARGETING THE SPHINGOLIPID BALANCE VIA ACID CERAMIDASE INHIBITION TO DECREASE GROWTH OF TMZ-RESISTANT GLIOBLASTOMA AND BLOCK MIGRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi75-vi75
Author(s):  
Cyntanna Hawkins ◽  
Amber Jones ◽  
Julia Ziebro ◽  
Emily Gordon ◽  
Catherine Libby ◽  
...  
Keyword(s):  
Cell Death ◽  
The Cancer Genome Atlas ◽  
Sphingolipid Metabolism ◽  
Acid Ceramidase ◽  
Cell Growth And Migration ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Key Enzyme ◽  
Resistant Patient ◽  
And Migration

Abstract Dysregulated sphingolipid metabolism is associated with many cancers; allowing cells to evade apoptosis through increases in sphingosine-1-phosphate (S1P) and decreases in ceramides. Ceramides can be hydrolyzed by ceramidases to sphingosine, which can then be phosphorylated by sphingosine kinases to S1P. S1P allows cells to evade apoptosis and increase migration, while shifts toward ceramides favor cell death. Glioblastoma (GBM) exhibits shifts in the sphingolipid balance towards S1P, contributing to chemoresistance and migration. Understanding of sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target the dysregulation. Acid ceramidase (ASAH1), a key enzyme in the production of S1P, is highly expressed in GBM and is associated with worse survival of GBM patients, as per The Cancer Genome Atlas data. To address the altered sphingolipid metabolism and therapeutic resistance in GBM, we explored the efficacy of pharmacologic and genetic inhibition of ASAH1 in both parental and temozolomide (TMZ)-resistant patient-derived xenografts. Cells were infected with ASAH1 shRNA or treated with ASAH1 inhibitors and assessed for cell growth and migration. Our work suggests that pharmacologic inhibition of ASAH1 induces cell death and that this effect is maintained in TMZ-resistant cells. Furthermore, we find a novel role for carmofur, an ASAH1 inhibitor, in the inhibition of GBM migration. Together, these data suggest the potential utility of normalizing the sphingolipid balance in the context of GBM TMZ resistance.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

scholarly journals SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Heyun Zhang ◽  
Zhangyu Zheng ◽  
Rongqin Zhang ◽  
Yongcong Yan ◽  
Yaorong Peng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Histone Methylation ◽  
Cell Growth And Migration ◽  
Histone 3 ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Proliferation And Migration

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. SET and MYND domain-containing protein 3 (SMYD3) has been shown to promote the progression of various types of human cancers, including liver cancer; however, the detailed molecular mechanism is still largely unknown. Here, we report that SMYD3 expression in HCC is an independent prognostic factor for survival and promotes the proliferation and migration of HCC cells. We observed that SMYD3 upregulated sphingosine-1-phosphate receptor 1 (S1PR1) promoter activity by methylating histone 3 (H3K4me3). S1PR1 was expressed at high levels in HCC samples, and high S1PR1 expression was associated with shorter survival. S1PR1 expression was also positively correlated with SMYD3 expression in HCC samples. We confirmed that SMYD3 promotes HCC cell growth and migration in vitro and in vivo by upregulating S1PR1 expression. Further investigations revealed that SMYD3 affects critical signaling pathways associated with the progression of HCC through S1PR1. These findings strongly suggest that SMYD3 has a crucial function in HCC progression that is partially mediated by histone methylation at the downstream gene S1PR1, which affects key signaling pathways associated with carcinogenesis and the progression of HCC.

scholarly journals Mitochondria-specific photoactivation to monitor local sphingosine metabolism and function

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Suihan Feng ◽  
Takeshi Harayama ◽  
Sylvie Montessuit ◽  
Fabrice PA David ◽  
Nicolas Winssinger ◽  
...  
Keyword(s):  
Time Course ◽  
Random Distribution ◽  
Direct Evidence ◽  
Subcellular Location ◽  
Sphingolipid Metabolism ◽  
Powerful Approach ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Function ◽  
Caged Molecules

Photoactivation ('uncaging’) is a powerful approach for releasing bioactive small-molecules in living cells. Current uncaging methods are limited by the random distribution of caged molecules within cells. We have developed a mitochondria-specific photoactivation method, which permitted us to release free sphingosine inside mitochondria and thereafter monitor local sphingosine metabolism by lipidomics. Our results indicate that sphingosine was quickly phosphorylated into sphingosine 1-phosphate (S1P) driven by sphingosine kinases. In time-course studies, the mitochondria-specific uncaged sphingosine demonstrated distinct metabolic patterns compared to globally-released sphingosine, and did not induce calcium spikes. Our data provide direct evidence that sphingolipid metabolism and signaling are highly dependent on the subcellular location and opens up new possibilities to study the effects of lipid localization on signaling and metabolic fate.

scholarly journals MicroRNA-21 Promotes Cell Growth and Migration by Targeting Programmed Cell Death 4 Gene in Kazakh’s Esophageal Squamous Cell Carcinoma

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Tao Liu ◽  
Qing Liu ◽  
Shutao Zheng ◽  
Xiangpeng Gao ◽  
Mang Lu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Luciferase Reporter ◽  
Cell Growth And Migration ◽  
Programmed Cell Death 4 ◽  
Negative Role ◽  
And Migration

Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth most common cause of cancer death. There are two main types of EC—squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). Although some advances in the exploration of its possible etiological mechanism were made recently including behaviors and environmental risk factors as well as gene alterations, the molecular mechanism underlying ESCC carcinogenesis and progression remains poorly understood. It has been reported that miR-21 was upregulated in most malignant cancers, the proposed mechanism of which was through suppressing expression of programmed cell death 4 (PDCD4). In present study, it is firstly reported that miR-21 was upregulated in Kazakh’s ESCC and that miR-21 played a negative role in regulating PDCD4 using in situ hybridization (ISH) and luciferase reporter approach. Morever, in model of ESCC xenografted nude mice, miR-21 maybe used as an effective target in the treatment. The present results demonstrated that miR-21 may be a potential therapeutic target in management of ESCC.

scholarly journals Roles of sphingosine-1-phosphate signaling in cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Peng Wang ◽  
Yonghui Yuan ◽  
Wenda Lin ◽  
Hongshan Zhong ◽  
Ke Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Signaling Cascades ◽  
Lipid Mediator ◽  
Downstream Signaling ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

AbstractThe potent pleiotropic lipid mediator sphingosine-1-phosphate (S1P) participates in numerous cellular processes, including angiogenesis and cell survival, proliferation, and migration. It is formed by one of two sphingosine kinases (SphKs), SphK1 and SphK2. These enzymes largely exert their various biological and pathophysiological actions through one of five G protein-coupled receptors (S1PR1–5), with receptor activation setting in motion various signaling cascades. Considerable evidence has been accumulated on S1P signaling and its pathogenic roles in diseases, as well as on novel modulators of S1P signaling, such as SphK inhibitors and S1P agonists and antagonists. S1P and ceramide, composed of sphingosine and a fatty acid, are reciprocal cell fate regulators, and S1P signaling plays essential roles in several diseases, including inflammation, cancer, and autoimmune disorders. Thus, targeting of S1P signaling may be one way to block the pathogenesis and may be a therapeutic target in these conditions. Increasingly strong evidence indicates a role for the S1P signaling pathway in the progression of cancer and its effects. In the present review, we discuss recent progress in our understanding of S1P and its related proteins in cancer progression. Also described is the therapeutic potential of S1P receptors and their downstream signaling cascades as targets for cancer treatment.

scholarly journals Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate

2012 ◽  
Vol 447 (1) ◽  
pp. 149-157 ◽  
Author(s):  
Yugesh Kharel ◽  
Mithun Raje ◽  
Ming Gao ◽  
Amanda M. Gellett ◽  
Jose L. Tomsig ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Lipid Mediator ◽  
Wild Type ◽  
Downstream Effects ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration ◽  
G Protein Coupled ◽  
Hybrid Mice

S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.

scholarly journals Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4307
Author(s):  
Laura Camacho ◽  
Amaia Zabala-Letona ◽  
Ana R. Cortazar ◽  
Ianire Astobiza ◽  
Asier Dominguez-Herrera ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Mrna Expression ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Sphingolipid Metabolism ◽  
Mrna Levels ◽  
Cell Growth And Migration ◽  
Ceramide Kinase ◽  
Pten Deletion ◽  
And Migration

Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, survival, and therapy resistance in cancer. Ceramide kinase (CERK) catalyzes the phosphorylation of ceramide to ceramide 1-phosphate, which regulates various cellular functions including cell growth and migration. Here we show that activated androgen receptor (AR) is a repressor of CERK expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. CERK was among the most prominent negatively correlated genes in our analysis. Interestingly, we demonstrated through various experimental approaches that activated AR reduces the mRNA expression of CERK: (i) expression of CERK is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce CERK mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific Pten deletion) results in elevated Cerk mRNA levels in prostate tissue. Mechanistically, we found that AR represses CERK through interaction with its regulatory elements and that the transcriptional repressor EZH2 contributes to this process. In summary, we identify a repressive mode of AR that influences the expression of CERK in PCa.

scholarly journals Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate

2011 ◽  
Vol 440 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Yugesh Kharel ◽  
Thomas P. Mathews ◽  
Amanda M. Gellett ◽  
Jose L. Tomsig ◽  
Perry C. Kennedy ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sphingosine Kinase ◽  
Rapid Onset ◽  
Physiological Functions ◽  
Extracellular Signal ◽  
Signalling Molecule ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1−/−) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1−/−, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

scholarly journals Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor–Induced Cell Death

2000 ◽  
Vol 192 (5) ◽  
pp. 601-612 ◽  
Author(s):  
Astrid Strelow ◽  
Katussevani Bernardo ◽  
Sabine Adam-Klages ◽  
Thomas Linke ◽  
Konrad Sandhoff ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Acid Sphingomyelinase ◽  
Acid Ceramidase ◽  
L929 Cells ◽  
Human Acid ◽  
Sphingosine 1 Phosphate ◽  
Dependent Cell ◽  
Necrosis Factor

Tumor necrosis factor (TNF) signals cell death and simultaneously induces generation of ceramide. To evaluate the contribution of ceramide to TNF-dependent cell death, we generated clones of the TNF-sensitive cell line L929 that constitutively overexpress human acid ceramidase (AC). Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation. In response to TNF, parental L929 cells display a significant increase in intracellular ceramide correlated with an “atypical apoptosis” characterized by membrane blebbing, DNA fragmentation and degradation of poly(ADP-ribose) polymerase despite a lack of caspase activity. These features are strongly reduced or absent in AC-overexpressing cells. Pharmacological suppression of AC with N-oleoylethanolamine restored the accumulation of intracellular ceramide as well as the sensitivity of the transfectants to TNF, implying that an enhanced metabolization of intracellular ceramide by AC shifts the balance between intracellular ceramide and SPP levels towards cell survival. Correspondingly, inhibition of ceramide production by acid sphingomyelinase also increased survival of TNF-treated L929 cells.

scholarly journals Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1573 ◽  
Author(s):  
Farzana Parveen ◽  
Daniel Bender ◽  
Shi-Hui Law ◽  
Vineet Kumar Mishra ◽  
Chih-Chieh Chen ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Tissue Expression ◽  
Human Diseases ◽  
Sphingolipid Metabolism ◽  
Acid Ceramidase ◽  
Sphingosine 1 Phosphate ◽  
Divergence Structure ◽  
Altered Lipid

Human pathologies such as Alzheimer’s disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3—which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.

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