Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death

Perryman, Michael S.; Tessier, Jérémie; Wiher, Timothy; O'Donoghue, Heather; McCracken, Alison N.; Kim, Seong M.; Nguyen, Dean Gia; Simitian, Grigor; Viana, Matheus P.; Rafelski, Susanne M.; Edinger, Aimee L.; Hanessian, Stephen

doi:10.1016/j.bmc.2016.07.038

Cited by 11 publications

(18 citation statements)

References 28 publications

(83 reference statements)

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“…Surface levels of CD98 are readily quantified using flow cytometry while antibodies recognizing the exofacial domains of other nutrient transporters are not generally available, most likely because glycosylation of the extracellular regions of these proteins sterically hinders antibody binding. As expected, the sphingolipids ceramide, sphingosine, FTY720 and 893 downregulated CD98 in mammalian cells (Guenther et al, 2008;Kim et al, 2016;Perryman et al, 2016;Romero Rosales et al, 2011;Fig. 1A,B and Fig.…”

Section: Resultssupporting

confidence: 80%

“…An 893 analog, 893-lactam, that lacks a charge on the pyrrolidine nitrogen fails to downregulate nutrient transporter proteins or induce vacuolation, which are both PP2A-dependent phenotypes ( Fig. S1; Chen et al, 2016;Perryman et al, 2016). Also, 893-lactam did not affect the localization of these recycling proteins (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…Unphosphorylated FTY720, in contrast, limits tumor cell growth and survival in vitro and in vivo by activating PP2A and disrupting endocytic trafficking (Kim et al, 2016;Romero Rosales et al, 2011). Unlike FTY720, the conformationally constrained FTY720 analog SH-BC-893 (893) does not activate S1P receptors, even in its phosphorylated form (Chen et al, 2016;Kim et al, 2016;Perryman et al, 2016). However, FTY720 and 893 produce identical disruptions in intracellular trafficking, and their IC50 values are closely matched, suggesting that effects on trafficking, not S1P receptors, are responsible for the anti-cancer activity of FTY720 (Kim et al, 2016;Romero Rosales et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

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Ramirez

Liu

et al. 2018

Journal of Cell Science

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Endogenous sphingolipids (ceramide) and related synthetic molecules (FTY720, SH-BC-893) reduce nutrient access by decreasing cell surface expression of a subset of nutrient transporter proteins. Here, we report that these sphingolipids disrupt endocytic recycling by inactivating the small GTPase ARF6. Consistent with reported roles for ARF6 in maintaining the tubular recycling endosome, MICAL-L1-positive tubules were lost from sphingolipid-treated cells. We propose that ARF6 inactivation may occur downstream of PP2A activation since: (1) sphingolipids that fail to activate PP2A did not reduce ARF6-GTP levels; (2) a structurally unrelated PP2A activator disrupted tubular recycling endosome morphology and transporter localization; and (3) overexpression of a phosphomimetic mutant of the ARF6 GEF GRP1 prevented nutrient transporter loss. ARF6 inhibition alone was not toxic; however, the ARF6 inhibitors SecinH3 and NAV2729 dramatically enhanced the killing of cancer cells by SH-BC-893 without increasing toxicity to peripheral blood mononuclear cells, suggesting that ARF6 inactivation contributes to the anti-neoplastic actions of sphingolipids. Taken together, these studies provide mechanistic insight into how ceramide and sphingolipid-like molecules limit nutrient access and suppress tumor cell growth and survival.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

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Ramirez

Liu

et al. 2018

Journal of Cell Science

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“…Vacuolation Assay-Vacuoles were quantified as in Perryman et al (20). Briefly, FL5.12 cells were treated as indicated for 3 h then pelleted by centrifuging at 2000 rpm for 3 min in a microfuge.…”

Section: Methodsmentioning

confidence: 99%

“…Although the synthetic sphingolipid FTY720 overcomes this problem, it also produces dose-limiting bradycardia at the concentrations required for tumor suppression by activating the sphingosine-1phosphate receptor 1(S1PR1) (33,34). SH-BC-893 is a structurally constrained analog of FTY720 that limits tumor growth in multiple model systems, including prostate and colorectal cancer, without activating S1PR1 (5,20,34,35). Both SH-BC-893 and C2-ceramide (N-Acetyl-sphingosine, Fig.…”

Section: Sh-bc-893 and C2-ceramide Produce Distinct Pp2a-dependent Amentioning

confidence: 99%

Dynamic Phosphoproteomics Uncovers Signaling Pathways Modulated by Anti-oncogenic Sphingolipid Analogs

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Piffaretti

et al. 2019

Molecular & Cellular Proteomics

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The anti-neoplastic sphingolipid analog SH-BC-893 starves cancer cells to death by down-regulating cell surface nutrient transporters and blocking lysosomal trafficking events. However, the actual mechanism of action giving rise to these phenotypes remains unclear. Here, dynamic phosphoproteomics was used to further understand how the activity of PP2A is affected following cell treatment with SH-BC-893. These analyses combined with functional assays identified the differential regulation of Akt and Gsk3b by SH-BC-893 and C2-ceramide as responsible for the vacuolation of cells by SH-BC-893 but not C2-ceramide.

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Cytotoxic and Pro-Apoptotic Properties of Ethyl-p-Methoxycinnamate and Its Hydrophilic Derivative Potassium-p-Methoxycinnamate

et al. 2018

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Purpose The present study was designed to investigate the underlying mechanism of cytotoxic and pro-apoptotic potential of ethyl-p-methoxycinnamate (EPMC) and its hydrophilic derivative potassium-p-methoxycinnamate (KPMC). Methods EPMC was isolated from Kaempferia galanga extract and its ethyl chain was replaced with potassium by KOH reflux to synthesize KPMC. The anti-proliferative effect of EPMC and KPMC was evaluated in six cancer cell lines and two normal cell lines by MTT assay. The inhibitory effects of the test compounds on colony formation, cell migration, chromatin condensation and mitochondrial membrane potential was further investigated in HCT-116 cells whereas their effect on caspase 3, 7, 8 and 9 activities was studied in HCT-116 and PC-3 cells. Results EPMC exhibited significant antiproliferative effect in all six cancer cell lines with maximum cytotoxicity against HCT-116 cells (selectivity index > 6). Our results showed significant inhibition of cell migration and colony formation in EPMC-treated colorectal carcinoma cells (HCT-116) when compared to the normal colon fibroblasts (CCD-18co). It exhibited dose dependent chromatin condensation and loss of mitochondrial membrane potential with subsequent induction of caspase 3/7 activity. KPMC did not inhibit the proliferation of either cell lines in MTT assay. Moreover, the cell migration, colony formation and caspase induction in KPMC-treated cells was comparable with the negative control. Conclusion The replacement of alkyl chain in EPMC by potassium resulted into the loss of cytotoxic and pro-apoptotic effects of EPMC.

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Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death

Cited by 11 publications

References 28 publications

Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

Dynamic Phosphoproteomics Uncovers Signaling Pathways Modulated by Anti-oncogenic Sphingolipid Analogs

Cytotoxic and Pro-Apoptotic Properties of Ethyl-p-Methoxycinnamate and Its Hydrophilic Derivative Potassium-p-Methoxycinnamate

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