Glucosylceramide Synthase Protects Glioblastoma Cells Against Autophagic and Apoptotic Death Induced by Temozolomide and Paclitaxel

Giussani, Paola; Bassi, Rajiv; Anelli, Viviana; Brioschi, L.; Zen, Federica De; Riccitelli, E.; Caroli, Manuela; Campanella, Rolando; Gaini, S. M.; Viani, Paola; Riboni, Laura

doi:10.3109/07357907.2011.629379

Cited by 42 publications

(37 citation statements)

References 46 publications

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“…Giussani and coworkers showed that glucosylceramide protects glioblastoma cells against autophagic and apoptotic by Temozolomide and Paclitaxel induced death, and the concomitant use of inhibitors of glucosylceramide synthase revert that resistance to enhance the cytotoxic effects of these drugs [7]. These two reports are consistent with experimental data MiaPaca-2 cell line.…”

Section: Discussionsupporting

confidence: 61%

Identification of cancer chemosensitivity by ODE and GMM modeling of heterogeneous cellular response to perturbations in fluorescent sphingolipid metabolism

Molina-Mora

Mora-Rodriguez

2016

2016 IEEE 36th Central American and Panama Convention (CONCAPAN XXXVI)

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Abstract-Cancer refers to a group of diseases in which cells display uncontrolled growth. Chemotherapy options are usually conditioned by generating resistance which is explained in part by the intrinsic heterogeneity of the population in the tumor. Because the study of resistance requires biosensors able to report the response at the single cell level, we propose to use fluorescently labeled SL to estimate pathway dynamics at the single cell level and investigate its possible application as gemcitabine (GMZ) response sensor in pancreatic cancer by comparing the dynamics between GMZ resistant (Panc-1, MiaPaca-2) and sensitive (BxPC3) cell lines. We used imaging flow cytometry to extract multiple image features and classify cells using gaussian-mixture model (GMM) to generate response fingerprints upon known perturbations. The results suggest that GMZ inhibits the Sphingomyelin-Synthase of BxPC3. Also, we constructed and fitted a dynamical mathematical model to simulate these perturbations and formulate cell line models revealing a striking heterogeneity among them. Predictions of the model respect the effect of GMZ in the accumulation of ceramide in BxPC3 and glucosyl-ceramide in MiaPaca-4 were confirm experimentally. Altogether, these results indicate that fluorescent-SL analogues can be used as sensors of chemotherapy in pancreatic cancer and reveal pathway dynamics between different cell lines, and its potential usage for the development of in vitro chemosensitivy assays able to dissect pathway dynamics to overcome resistance.

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Section: Discussionsupporting

confidence: 61%

Identification of cancer chemosensitivity by ODE and GMM modeling of heterogeneous cellular response to perturbations in fluorescent sphingolipid metabolism

Molina-Mora

Mora-Rodriguez

2016

2016 IEEE 36th Central American and Panama Convention (CONCAPAN XXXVI)

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“…SphK1, S1P and its receptors play a vital role in induction of cancer chemoresistance. Selection of TMZ-resistant GBM cells has been shown to be associated not only with an increase in GlcCer synthase [ 138 ], but also with SphK1 expression [ 149 ]. However, in spite of GSC inhibition hindering resistance to TMZ-induced autophagic death [ 138 ], SphK1 down-regulation was found to have a similar proapoptotic effect on TMZ-sensitive and -resistant cells [ 149 ].…”

Section: Sphingolipids In Gbm Cell Survival and Death Resistancementioning

confidence: 88%

“…Interestingly, enhanced lethality correlated with increased autophagy that was dependent on the expression of CerS6. In addition, exposure of human GBM cells to TMZ promoted autophagic cell death by the production of ceramide [ 138 ].…”

Section: Ceramide In Necrotic and Autophagic Death Of Gbm Cellsmentioning

confidence: 99%

“…It was found that resistant cells rapidly consume ceramide upon gemcitabine treatment, and the activity of GlcCer synthase mediates ceramide consumption. In addition, selection of drug-resistant GBM cell by gradual exposure to increasing drug concentrations, revealed an up-regulation of GlcCer synthase protects GBM cells against autophagic and apoptotic death induced by TMZ and paclitaxel, and contributes to their chemoresistance [ 138 ].…”

Section: Sphingolipids In Gbm Cell Survival and Death Resistancementioning

confidence: 99%

“…Selection of TMZ-resistant GBM cells has been shown to be associated not only with an increase in GlcCer synthase [ 138 ], but also with SphK1 expression [ 149 ]. However, in spite of GSC inhibition hindering resistance to TMZ-induced autophagic death [ 138 ], SphK1 down-regulation was found to have a similar proapoptotic effect on TMZ-sensitive and -resistant cells [ 149 ]. A possible explanation of this difference may reside in the heterogeneity of GBM cells, and particularly in the different intrinsic resistance of the GBM models used in these studies, which is also refl ected by the different mechanisms of death, autophagic and apoptotic, exerted by TMZ and SphK1 inhibition.…”

Section: Sphingolipids In Gbm Cell Survival and Death Resistancementioning

confidence: 99%

See 2 more Smart Citations

The Role and Function of Sphingolipids in Glioblastoma Multiforme

Hadi

Vito

Marfia

et al. 2015

Bioactive Sphingolipids in Cancer Biology and Therapy

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Aberrations in sphingolipid metabolism and thus levels have been implicated in promoting the aggressiveness of glioblastoma multiforme, one of the most lethal cancers in humans. A major player is sphingosine-1-phosphate, that pressures GBM cells to exhibit its hallmarks, leading to increased proliferation, invasiveness, stemness, angiogenesis and death resistance, this indicating a fi ne balance and interplay between S1P function and this malignancy. To the opposite GBM are organized to maintain low their ceramide and sphingomyelin levels, which in turn lead to a loss of growth control and to a gain of death resistance. While the mechanisms of these alterations are emerging, the sphingolipid signaling pathway has been implicated in controlling GBM action and mass, and in mediating the link of malignancy. Here we describe and discuss the current understanding on how GBM cells arm themselves with the abilities of manipulating sphingolipids, especially sphingosine-1-phosphate and ceramide, and how these alterations, through differential interactions, regulate different signaling

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Cross‐talk between sphingosine‐1‐phosphate and EGFR signaling pathways enhances human glioblastoma cell invasiveness

et al. 2018

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We show that glioblastoma multiform (GBM) cells overexpressing the constitutively active form of the epidermal growth factor receptor [epidermal growth factor receptor variant III (EGFRvIII) and U87MG human GBM cell line overexpressing EGFRvIII (EGFR+) cells] possess greater invasive properties and have higher levels of extracellular sphingosine-1-phosphate (S1P) and increased sphingosine kinase-1 (SK1) activity than the empty vector-expressing cells. Notably, the inhibition of SK1 or S1P receptors decreases the invasiveness of EGFR+ cells. Moreover, EGFR and MEK1 inhibitors reduce both SK1 activation and cell invasion, suggesting that the enhanced invasiveness observed in the EGFR+ cells depends on the increased S1P secretion, downstream of the EGFRvIII-ERK-SK1-S1P pathway. Altogether, the results of the present study indicate that, in GBM cells, EGFRvIII is connected with the S1P signaling pathway to enhance cell invasiveness and tumor progression.

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Glucosylceramide Synthase Protects Glioblastoma Cells Against Autophagic and Apoptotic Death Induced by Temozolomide and Paclitaxel

Cited by 42 publications

References 46 publications

Identification of cancer chemosensitivity by ODE and GMM modeling of heterogeneous cellular response to perturbations in fluorescent sphingolipid metabolism

Identification of cancer chemosensitivity by ODE and GMM modeling of heterogeneous cellular response to perturbations in fluorescent sphingolipid metabolism

The Role and Function of Sphingolipids in Glioblastoma Multiforme

Cross‐talk between sphingosine‐1‐phosphate and EGFR signaling pathways enhances human glioblastoma cell invasiveness

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