FTY720 enhances TRAIL-mediated apoptosis by up-regulating DR5 and down-regulating Mcl-1 in cancer cells

Woo, Seon Min; Seo, Bo Ram; Min, Kyoung‐jin; Kwon, Taeg Kyu

doi:10.18632/oncotarget.3426

Cited by 18 publications

(16 citation statements)

References 50 publications

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“…Studies from our group demonstrated that SPL expression is high in the intestinal epithelium but downregulated in murine adenomas and human colorectal cancers [ 11 , 61 ]. This finding, combined with a growing appreciation for the key role S1P signaling plays in colon cancer [ 156 – 159 ], prompted us to investigate the potential effect of gut epithelial SGPL1 disruption on the development of CAC. Toward that end, we generated an inducible intestinal epithelium-specific SPL KO mouse (SPL GutKO ) using Cre/lox technology [ 10 , 147 ].…”

Section: S1p Signaling and Inflammationmentioning

confidence: 99%

S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

Kumar

Zamora-Pineda

Degagné

et al. 2017

Mediators of Inflammation

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Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes.

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Section: S1p Signaling and Inflammationmentioning

confidence: 99%

S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

Kumar

Zamora-Pineda

Degagné

et al. 2017

Mediators of Inflammation

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“…FTY720 is a synthetic compound produced by modification of a metabolite from I. sinclairii and has strong anti-cancer activity. For example, FTY720 induces cell death in multiple cancer cells [ 1 , 2 , 3 , 4 ] and sensitizes cancer cells to chemotherapy and radiotherapy [ 5 , 6 , 7 , 8 ]. Interestingly, FTY720 has also been seen to increase non-apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Min

Kwon

2020

Cancers

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FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.

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“…S1P is a bioactive lipid with oncogenic functions that promoting tumor cell growth and invasion. SphK1 has received increased attention during the past years [ 5 – 6 ]. SphK1 is overexpressed in various cancers, and the upregulation of SphK1 is associated with poor prognosis in many types of human cancers.…”

Section: Introductionmentioning

confidence: 99%

Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression

Dong

Huang

et al. 2015

Oncotarget

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Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.

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FTY720 enhances TRAIL-mediated apoptosis by up-regulating DR5 and down-regulating Mcl-1 in cancer cells

Cited by 18 publications

References 50 publications

S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression

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