Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

Camp, E. Ramsay; Patterson, Logan; Kester, Mark; Voelkel‐Johnson, Christina

doi:10.1080/15384047.2017.1345396

Cited by 22 publications

(23 citation statements)

References 114 publications

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“…Moreover, compared to other gut metabolites, the source of sphingolipids can be mainly attributed to the host, as only few bacterial taxa produce sphingolipids 60 . Multiple modulators and bioactive sphingolipids are currently in clinical trials for gastrointestinal diseases 61 , 62 and might hold value for preventing NEC. The presence of higher levels of sphingolipids might also be related to their reported bactericidal activity against multiple Gram-negative and Gram-positive bacteria 63 and indirectly by affecting NOD2 recruitment and subsequent innate immunity response 64 .…”

Section: Discussionmentioning

confidence: 99%

Gut Sphingolipid Composition as a Prelude to Necrotizing Enterocolitis

Rusconi

Jiang

Sidhu

et al. 2018

Sci Rep

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Necrotizing enterocolitis (NEC) remains a major challenge in neonatology. Little is known about NEC pathophysiology apart from the presence of pre-event gut dysbiosis. Here, we applied broad range metabolomics to stools obtained 1–5 days before NEC developed from 9 cases (9 samples) and 19 (32 samples) controls matched for gestational age at birth and birth weight. The 764 identified metabolites identified six pathways that differ between cases and controls. We pursued sphingolipid metabolism because cases had decreased ceramides and increased sphingomyelins compared to controls, and because of the relevance of sphingolipids to human inflammatory disorders. Targeted analysis of samples from 23 cases and 46 controls confirmed the initial broad range observations. While metabolites provided only 73% accuracy of classification by machine learning, hierarchical clustering defined a sphingolipid associated grouping that contained 60% of the cases but only 13% of the controls, possibly identifying a pathophysiologically distinct subset of NEC. The clustering did not associate with any of the analyzed clinical and sample variables. We conclude that there are significant changes in sphingolipid metabolism components in pre-NEC stools compared to controls, but our data urge circumspection before using sphingolipids as broadly applicable predictive biomarkers.

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Section: Discussionmentioning

confidence: 99%

Gut Sphingolipid Composition as a Prelude to Necrotizing Enterocolitis

Rusconi

Jiang

Sidhu

et al. 2018

Sci Rep

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“…Among sphingolipids constituting cell membranes, ceramide, a central molecule in sphingolipid metabolism and signaling pathways, is a typical sphingolipid exhibiting cytotoxicity [ 16 , 17 , 18 , 19 , 20 , 21 ]. In cancer cells, its levels and signaling are usually suppressed by the overexpression of ceramide-metabolizing enzymes or down-regulation of ceramide-generating enzymes.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

Yura

Masui

Hamada

2020

Cancers

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In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.

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“… 3 In spite of advances in surgery and adjuvant chemotherapies, which remain the standard treatment options, the prognosis for patients with CRC still remains poor. 4 Therefore, new diagnostic markers or therapeutic targets for CRC are critical.…”

Section: Introductionmentioning

confidence: 99%

MiR-199a-5p Inhibits the Growth and Metastasis of Colorectal Cancer Cells by Targeting ROCK1

Zhu

Zhou

Dong

et al. 2018

Technol Cancer Res Treat

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Mounting evidence indicates that microRNAs play important roles in the development of various cancers. Aberrant expression of microRNA-199a-5p has been frequently reported in cancer studies; however, the mechanistic details of the role of microRNA-199a-5p in colorectal cancer still remain unclear. Our study aimed to explore the role of microRNA-199a-5p in colorectal cancer cells by targeting Rho-associated coiled coil-containing protein kinase 1. Here, we showed that microRNA-199a-5p was significantly downregulated in colorectal cancer cell lines and tissue samples and was associated with a poor prognostic phenotype. MicroRNA-199a-5p suppressed colorectal cancer cell proliferation, migration, and invasion and induced cell apoptosis. Moreover, we identified Rho-associated coiled coil-containing protein kinase 1 as the direct target of microRNA-199a-5p using luciferase and Western blot assays. Importantly, Rho-associated coiled coil-containing protein kinase 1 overexpression rescued the microRNA-199a-5p-induced suppression of proliferation, migration, and invasion of colorectal cancer cells. Furthermore, the overexpression of microRNA-199a-5p inhibited tumor growth and metastasis by inactivating the phosphoinositide 3-kinase/AKT and Janus kinase 1/signal transducing activator of transcription signaling pathways through downregulation of Rho-associated coiled coil-containing protein kinase 1. Altogether, microRNA-199a-5p/Rho-associated coiled coil-containing protein kinase 1 may be a potential therapeutic target for colorectal cancer therapy.

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Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

Cited by 22 publications

References 114 publications

Gut Sphingolipid Composition as a Prelude to Necrotizing Enterocolitis

Gut Sphingolipid Composition as a Prelude to Necrotizing Enterocolitis

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

MiR-199a-5p Inhibits the Growth and Metastasis of Colorectal Cancer Cells by Targeting ROCK1

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