Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance MCF-7 cells

Shammout, Ola D.A.; Ashmawy, Naglaa S.; Shakartalla, Sarra B.; Altaie, Alaa Muayad; Semreen, Mohammad H.; Omar, Hany A.; Soliman, Sameh S. M.

doi:10.1371/journal.pone.0258363

Cited by 9 publications

(9 citation statements)

References 56 publications

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“…In this process, the cofactor pyridoxal-5-phosphate plays a crucial role which is synthetized partially from glutamate and pyruvate. Serine can then be integrated in the sphingolipid metabolism which was shown to be important in cancer cell proliferation [ 31 ], ROS signalling [ 32 , 33 ] and development of chemoresistance [ 34 ]. Also, the import of cystine by the antiporter xCT (SLC7A11) is mediated by the secretion of glutamate and represents an important step for glutathione synthesis [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

et al. 2022

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The mitochondrial enzyme fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) was identified to be upregulated in breast cancer tissues. Here, we show that FAHD1 is indispensable for the survival of BT-20 cells, representing the basal breast cancer cell type. A lentiviral knock-down of FAHD1 in the breast cancer cell lines MCF-7 and BT-20 results in lower succinate dehydrogenase (complex II) activity. In luminal MCF-7 cells, this leads to reduced proliferation when cultured in medium containing only glutamine as the carbon source. Of note, both cell lines show attenuated protein levels of the enzyme glutaminase (GLS) which activates programmed cell death in BT-20. These findings demonstrate that FAHD1 is crucial for the functionality of complex II in breast cancer cells and acts on glutaminolysis in the mitochondria.

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Section: Discussionmentioning

confidence: 99%

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

et al. 2022

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“…Recently, Cruz et al showed beneficial effects of ceramide use in nanomedicine, targeting it in combination with doxorubicin, within liposomes, to MDA-MB-231 cells [ 50 ]. MCF cells are able to escape from the ceramide-related apoptosis by the activation of ganglioside synthesis [ 51 ]. In our study, compound 1 significantly increased early and late apoptosis in MDA-MB-231 cells, but only late apoptosis in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Novel Thieno [2,3-b]pyridine Anticancer Compound Lowers Cancer Stem Cell Fraction Inducing Shift of Lipid to Glucose Metabolism

Pervan

Marijan²,

Markotić³

et al. 2022

IJMS

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Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC–MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.

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“…Their findings suggest that SGMS2 promotes EMT through activation of the TGF-ß/SMAD pathway, more specifically, by increasing TGF-ß1 secretion [ 83 ]. An increase in ceramide turnover to SM is also an important feature of chemotherapy resistance in BC [ 84 ].…”

Section: The Other Role Of Ceramides: Conversion To Pro-survival Sphi...mentioning

confidence: 99%

“…Considering the role of ceramides in cell death and the role of ceramide downstream metabolites in cell proliferation and survival, it is plausible that therapy-resistant cells take certain measures to keep their ceramide levels regulated. Recently, Shammout and colleagues compared doxorubicin-sensitive and -resistant MCF-7 cells and found that the doxorubicin-resistant cells maintain an increased level of SM and decreased levels of ceramides, dihydroceramides, and HexCers [ 84 ]. Similarly, our profiling study of tamoxifen-sensitive and -resistant cells also found decreased ceramide and HexCers levels in tamoxifen-resistant cells, although SM and dihydroceramide levels were found to be unaltered [ 91 ].…”

Section: Therapeutic Implications Of Ceramides In Breast Cancermentioning

confidence: 99%

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

Pal

Atilla‐Gokcumen

Frasor

2022

IJMS

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One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.

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Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance MCF-7 cells

Cited by 9 publications

References 56 publications

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

Novel Thieno [2,3-b]pyridine Anticancer Compound Lowers Cancer Stem Cell Fraction Inducing Shift of Lipid to Glucose Metabolism

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

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