Targeting the Sphingolipid Rheostat in Gliomas

Zaibaq, Faris; Dowdy, Tyrone; Larion, Mioara

doi:10.3390/ijms23169255

Cited by 16 publications

(12 citation statements)

References 196 publications

(352 reference statements)

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“…In IDH1 mut gliomas, the S1P-to-ceramide rheostat is tilted towards high ceramide levels (Fig. 1A, 12,13 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we demonstrated that in IDH1 mut glioma, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid (MUFA) levels 11 . These increased MUFA are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis 12,13 . Therefore, for the first time, it has been described the rheostat imbalance in IDH mut gliomas, to be the opposite of that known in IDH wt gliomas.…”

Section: Introductionmentioning

confidence: 99%

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Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

Muley,

Dowdy,

Zaibaq

et al. 2024

Preprint

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Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut)and 1p/19q co-deletions. Previously, we reported that in IDH1mut gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDHmut-specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1mut oligodendroglioma. We demonstrated an IDH1mut-specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1mut and should be considered in the future.

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“…In IDH1 mut gliomas, the S1P-to-ceramide rheostat is tilted towards high ceramide levels (Fig. 1A, 12,13 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

Muley,

Dowdy,

Zaibaq

et al. 2024

Preprint

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“…Our demonstration that the knock-down of SMPD3 , the critical gene involved in ceramide production, increases the proliferative status of IDH-O cells in vitro and in vivo is in keeping with the sphingolipid rheostat switching in a pro-proliferative (i.e., S1P-producing) direction. Given the importance of this lipid conversion in regulating the growth of multiple tumor types, it is not surprising that drugs targeting the sphingolipid rheostat have now reached clinical trials for glioma patients 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in experimental models such as the rat C6 glioma cell line, expression of Smpd3 inhibits tumour growth 16 . These data suggest that the sphingolipid rheostat is shifted in opposite directions in IDH-mutant versus IDH-wildtype gliomas – with the balance towards pro-proliferative in GBM and anti-proliferative/pro-apoptotic in IDH-O and IDH-A 10-12 .…”

Section: Introductionmentioning

confidence: 90%

“…One factor implicated in distinguishing IDH-wild-type versus IDH-mutant glioma growth rates is the "sphingolipid rheostat", which controls the balance between sphingosine-1-phosphate (S1P), a pro-proliferative lipid second messenger, and ceramide, which suppresses cell growth and induces apoptosis [10][11][12] . Ceramide acts cell-autonomously to suppress cell proliferation and induce cell death through autocrine signaling and is also secreted, impacting surrounding cells via paracrine signaling.…”

Section: Introductionmentioning

confidence: 99%

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SMPD3suppresses IDH mutant tumor growth via dual autocrine-paracrine roles

Balakrishnan

Adnani

Chinchalongporn

et al. 2020

Preprint

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Oligodendrogliomas are lower-grade, slow-growing gliomas that are ultimately fatal. Although driver mutations are known, the mechanisms underlying their signature slow growth rates are poorly understood. We found evidence for intra-tumoral interactions between neoplastic and nonneoplastic cells in oligodendroglioma tissues. To further study these cell interactions, we used two patient-derived oligodendroglioma cell lines of lower and higher aggressivity. Both oligodendroglioma cell lines released extracellular vesicles that had cytotoxic effects on nonneoplastic and neoplastic cells, but each had distinct vesicular proteomes. Consistent with extracellular vesicles mediating growth inhibitory effects in oligodendrogliomas, higher expression levels of several extracellular vesicle biogenesis genes (SMPD3,TSG101, STAM1) correlates with longer survival in oligodendroglioma patients. Furthermore, SMPD3 overexpression slows oligodendroglioma cell growth in culture. Conversely, SMPD3 knockdown enhances oligodendroglioma proliferation in vitro, in murine xenografts, and in human cerebral organoid co-cultures. Oligodendroglioma-derived extracellular vesicles thus mediate tumor cell microenvironmental interactions that contribute to low aggressivity.

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RETRACTED ARTICLE: Integration of clinical and spatial data to explore lipid metabolism-related genes for predicting prognosis and immune microenvironment in gliomas

Zhou

et al. 2023

Funct Integr Genomics

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Lipid metabolism is crucial to tumor growth and immune microenvironment as well as drug sensitivity in glioma. Identifying prognostic indicators of glioma and elucidating the mechanisms of glioma progression is for improving glioma patient prognosis. In this study, we investigated the role and prognostic value of metabolism-related genes in glioma by GEO, CGGA, and TCGA. Based on clinical data and transcriptome data, We found that the expression pattern of three major pathways of lipid metabolism is fatty acid high -phospholipid high -triglyceride low , which is associated with better prognosis and immune in ltration. Using the related genes of these three pathways constructed a prognostic model, and the model showed stability and e ciency in the test set and validation set. In the spatial transcriptome of glioma patients, the microenvironment of the regions with high expression of risk gene CAV1 and SCD is in a state of hypoxia, EMT, and cell cycle arrest, and thus can be used as markers of metabolic reprogramming in the tumor microenvironment. In the high-risk group, M0 macrophages and M1 macrophages were signi cantly enriched, and the risk score was signi cantly correlated with gene mutation and methylation. screened the sensitive drugs corresponding to different risk genes. This study provided novel insights into the differential immune microenvironment with different metabolic expression patterns and highlighted the spatial and temporal synergy of tumor progression and metabolic reprogramming.

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Targeting the Sphingolipid Rheostat in Gliomas

Cited by 16 publications

References 196 publications

Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors

SMPD3suppresses IDH mutant tumor growth via dual autocrine-paracrine roles

RETRACTED ARTICLE: Integration of clinical and spatial data to explore lipid metabolism-related genes for predicting prognosis and immune microenvironment in gliomas

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