FTY-720 induces apoptosis in neuroblastoma via multiple signaling pathways

Lange, Ingo; Espinoza-Fuenzalida, Italo; Ali, Mourad W.; Serrano, Laura Espana; Koomoa, Dana-Lynn T.

doi:10.18632/oncotarget.22452

Cited by 14 publications

(17 citation statements)

References 34 publications

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“…Neuroblastoma (Nbl) is an embryonal tumour, originating from progenitor cells of the sympathetic nervous system, and is the most common extra-cranial solid tumour of childhood [1][2][3] . Nbl accounts for 7% of malignancies from birth to 14-y of age 4 and 12% of cancer deaths in children.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin

et al. 2018

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Cisplatin (CDDP) is a widely used agent in the treatment of neuroblastoma. Unfortunately, the development of acquired chemoresistance limits its clinical use. To gain a detailed understanding of the mechanisms underlying the development of such chemoresistance, we comparatively analysed established cisplatin-resistant neuroblastoma cell line (UKF-NB-4 CDDP) and its sensitive counterpart (UKF-NB-4). First, using viability screenings, we confirmed the decreased sensitivity of tested cells to cisplatin and identified a cross-resistance to carboplatin and oxaliplatin. Then, the proteomic signatures were analysed using nanoLC MS/MS. Among the proteins responsible for UKF-NB-4 CDDP chemoresistance, ion channels transport family proteins, ABC superfamily proteins, SLC-mediated trans-membrane transporters, proteasome complex subunits and V-ATPases were identified. Moreover, we detected markedly higher proteasome activity in UKF-NB-4 CDDP cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4 CDDP to CDDP. Our results indicate that lysosomal sequestration and proteasome activity may be one of key mechanisms responsible for intrinsic chemoresistance of neuroblastoma to CDDP.

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Section: Introductionmentioning

confidence: 99%

Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin

et al. 2018

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“…These effects may not only be associated with the neuroprotective benefits of this drug 40 but also, its therapeutic effects in ischemia, excitotoxicity and memory recovery 41–43 . Nevertheless, this drug could also negatively affect neurons, inducing apoptosis by altering calcium signalling and mitochondrial membrane potentials, effects that could be useful to sensitize neuroblastoma cells to anti-.neoplastic drugs 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, more evidence appeared in recent years suggesting that this compound accumulates in cells of the CNS, modulating the activity of neurons and astrocytes 14,15 , potentially making it suitable to treat a variety of neurological syndromes like ischemia, stroke and neurodegeneration 16–18 . Furthermore, this drug has been also proposed for the treatment of neuronal cancers given its potential to induce the death of neuroblastoma cells 19 .…”

Section: Introductionmentioning

confidence: 99%

Multiple sclerosis drug FTY-720 toxicity is mediated by the heterotypic fusion of organelles in neuroendocrine cells

Giménez-Molina

García-Martínez

Villanueva

et al. 2019

Sci Rep

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FTY-720 (Fingolimod) was one of the first compounds authorized for the treatment of multiple sclerosis. Among its other activities, this sphingosine analogue enhances exocytosis in neuroendocrine chromaffin cells, altering the quantal release of catecholamines. Surprisingly, the size of chromaffin granules is reduced within few minutes of treatment, a process that is paralleled by the homotypic fusion of granules and their heterotypic fusion with mitochondria, as witnessed by dynamic confocal and TIRF microscopy. Electron microscopy studies support these observations, revealing the fusion of several vesicles with individual mitochondria to form large, round mixed organelles. This cross-fusion is SNARE-dependent, being partially prevented by the expression of an inactive form of SNAP-25. Fused mitochondria exhibit an altered redox potential, which dramatically enhances cell death. Therefore, the cross-fusion of intracellular organelles appears to be a new mechanism to be borne in mind when considering the effect of FTY-720 on the survival of neuroendocrine cells.

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“…Many mechanisms have been proposed for the effects of FTY720, including activation of PP2A [21] , [22] , generation of reactive oxygen species [44] , [45] , [46] , and inhibition of sphingosine kinase 1 (SphK1) [47] , [48] . Li and others showed that FTY720 inhibited sphingosine kinase 2 in neuroblastoma [49] , and Lange et al studied the effects on calcium channel signaling in neuroblastoma [50] , but neither group explored whether PP2A activation was involved [49] , [50] . In the current study, we found that FTY720 treatment significantly increased PP2A activity in neuroblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

Investigation of PP2A and Its Endogenous Inhibitors in Neuroblastoma Cell Survival and Tumor Growth

Williams

Garner

Waters

et al. 2019

Translational Oncology

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High-risk neuroblastoma continues to carry a poor prognosis. Nearly 50% of these tumors relapse following extensive treatment regimens. Protein phosphatase 2A (PP2A), a tumor suppressor, has been shown to be downregulated in many human cancers via multiple mechanisms including upregulation of its endogenous inhibitors, I2PP2A or CIP2A. We hypothesized that inhibition of the endogenous PP2A inhibitors or activation of PP2A would decrease tumorigenicity in human neuroblastoma cells. Four human neuroblastoma cell lines were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was confirmed by immunoblotting. PP2A activation was measured via phosphatase activation assay. Multiple parallel methods including siRNA inhibition of the endogenous PP2A inhibitors and pharmacologic activation of PP2A were utilized. Cell viability, proliferation, migration, and invasion assays were performed. In vivo studies were utilized to determine the effects of PP2A activation on neuroblastoma tumor growth. Inhibition of the endogenous inhibitors of PP2A or pharmacologic activation of PP2A with the PP2A activator FTY720 led to decreased neuroblastoma cell viability, proliferation, migration, and invasion. Treatment of mice bearing SK-N-AS or SK-N-BE(2) neuroblastoma tumors with FTY720 resulted in a significant decrease in tumor growth compared to vehicle-treated animals. In conclusion, activation of PP2A may provide a novel therapeutic target for neuroblastoma.

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FTY-720 induces apoptosis in neuroblastoma via multiple signaling pathways

Cited by 14 publications

References 34 publications

Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin

Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin

Multiple sclerosis drug FTY-720 toxicity is mediated by the heterotypic fusion of organelles in neuroendocrine cells

Investigation of PP2A and Its Endogenous Inhibitors in Neuroblastoma Cell Survival and Tumor Growth

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