Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Vykoukal, Jody; Fahrmann, Johannes F.; Gregg, Justin R.; Tang, Zhe; Basourakos, Spyridon P.; Irajizad, Ehsan; Park, Sanghee; Yang, Guang; Creighton, Chad J.; Fleury, Alia; Mayo, Jeffrey; Paulucci-Holthauzen, Adriana; Dennison, Jennifer B.; Murage, Eunice; Peterson, Christine B.; Davis, John W.; Kim, Jeri; Hanash, Samir M.; Thompson, Timothy C.

doi:10.1038/s41467-020-17645-z

Cited by 61 publications

(64 citation statements)

References 67 publications

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“…5A and suggests that both eliglustat and Genz-123346 are indeed autophagic flux inhibitors as opposed to an inducer. In addition, the findings that eliglustat increased LC3-II levels and mitochondrial mass, and, the co-localization of mitochondria and lysosomes in prostate cancer cells ( 32 ) are consistent with our data. We observed an increase of LC3-II but also an increase of p62 (Fig.…”

Section: Discussionsupporting

confidence: 92%

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The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

Leng

Zhang

et al. 2021

Preprint

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Multiple myeloma (MM) is a fatal hematological malignancy, where the majority of patients are diagnosed with, or develop, destructive and debilitating osteolytic bone lesions. Current treatments for MM bone disease such as the bisphosphonate zoledronic acid can result in deleterious side effects at high doses. In this study, eliglustat, an FDA approved glycosphingolipid inhibitor, was shown to reduce MM bone disease in preclinical models of MM. Mechanistically, eliglustat alters the lipid composition and plasma membrane fluidity and acts as an autophagy flux inhibitor in bone-resorbing osteoclasts (OC). Autophagic degradation of the signaling molecule TRAF3 is key step in OC differentiation; this was prevented by eliglustat in OC precursors. In addition, eliglustat works depend on TRAF3 in vivo. Furthermore, the combination of eliglustat and zoledronic acid was found to have an additive effect to reduce MM bone disease, suggesting the potential for combination therapies that would allow for drug dose reductions. Taken together, this project identifies a novel mechanism in which glycosphingolipid inhibition reduces osteoclastogenesis via autophagy and highlights the translational potential of eliglustat for the treatment of bone loss disorders such as MM.

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Section: Discussionsupporting

confidence: 92%

“…4, D and E). D-PDMP, a known inhibitor of GCS ( 32 ), similarly reduced aggregate abundance expression on RAW264.7 cells and served as positive control (Fig. 4E).…”

Section: Resultsmentioning

confidence: 91%

The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

Leng

Zhang

et al. 2021

Preprint

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“…Here, we hypothesized that due to the extremely high expression of GD2 in H3K27M-mutant DMG, the glycosphingolipids metabolism is particularly active in these cells and that its perturbation via inhibition of the glucosylceramide synthase could be lethal. The sphingolipid oncometabolism, which has recently been described as a metabolic vulnerability in cancer and tumor growth, was inhibited by eliglustat in an in vitro and a preclinical in vivo model of prostate cancer [ 71 ]. In line with our data (IC50 45–61.5 µM), the cytotoxic concentration of eliglustat required to inhibit the prostatic cancer cell line RM-9 in vitro was 128 µM.…”

Section: Discussionmentioning

confidence: 99%

“…This could be important, because gangliosides are needed for neural cell function. However, neurotoxicity under treatment with eliglustat was not described in C57BL/6N mice without enzymatic dysfunction [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Wingerter

Malki

Sandhoff

et al. 2021

Cancers

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The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

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“…Additionally, the carbohydrate and lipid metabolism have always been closely related to cancer cell proliferation and migration [ 51 ]. The KEGG pathway enrichment of coding genes harboring the hyper-methylated peaks in IMPA samples was related to the PPAR signaling pathways (Fig.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

et al. 2021

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Background Invasive malignant pleomorphic adenoma (IMPA) is a highly invasive parotid gland tumor and lacks effective therapy. N6-Methyladenosine (m6A) is the most prevalent post-transcriptional modification of mRNAs in eukaryotes and plays an important role in the pathogenesis of multiple tumors. However, the significance of m6A-modified mRNAs in IMPA has not been elucidated to date. Hence, in this study, we attempted to profile the effect of IMPA in terms of m6A methylation in mRNA. Methods Methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were utilized to acquire the first transcriptome-wide profiling of the m6A methylome map in IMPA followed by bioinformatics analysis. Results In this study, we obtained m6A methylation maps of IMPA samples and normal adjacent tissues through MeRIP-seq. In total, 25,490 m6A peaks associated with 13,735 genes were detected in the IMPA group, whereas 33,930 m6A peaks associated with 18,063 genes were detected in the control group. Peaks were primarily enriched within coding regions and near stop codons with AAACC and GGAC motifs. Moreover, functional enrichment analysis demonstrated that m6A-containing genes were significantly enriched in cancer and metabolism relevant pathways. Furthermore, we identified a relationship between the m6A methylome and the RNA transcriptome, indicating a mechanism by which m6A modulates gene expression. Conclusions Our study is the first to provide comprehensive and transcriptome-wide profiles to determine the potential roles played by m6A methylation in IMPA. These results may open new avenues for in-depth research elucidating the m6A topology of IMPA and the molecular mechanisms governing the formation and progression of IMPA.

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Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Cited by 61 publications

References 67 publications

The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Comprehensive analysis of the transcriptome‐wide m6A methylome in invasive malignant pleomorphic adenoma

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