Ceramide-orchestrated signalling in cancer cells

Morad, Samy A.F.; Cabot, Myles C.

doi:10.1038/nrc3398

Cited by 884 publications

(516 citation statements)

References 197 publications

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“…Another contributing outcome derived from the TGN trafficking brake likely involves an altered metabolism of ceramide and its derivatives, which is supported by a significant impact by SG on transport of ceramide and synthesis of its derivatives in post-Golgi organelles, whose intracellular accumulation induces apoptosis with multiple but poorly defined mechanisms. 41,42 Notably, expression of membrane glycoprotein receptors such as EGFR and CD98hc was not significantly altered by SG, indicating different post-Golgi routes or mechanisms involved in the transportation and trafficking of complex lipids and of membrane receptors. In addition, protein glycosylation plays important roles in the dimerization and activation of various receptors, 43 and desialylation by schweinfurthins could be also part of the anti-proliferative mechanism of a TGN trafficking brake.…”

Section: Discussionmentioning

confidence: 99%

“…Sustained ER stress is known to cause cell growth inhibition and cell apoptosis though multiple mechanisms. 41 Interestingly, ER stress has recently been reported to induce AKT phosphorylation inhibition at Thr-308, but not Ser-473, 30 and thus the AKT phosphorylation inhibition by schweinfurthins could also be partly contributed by the induced ER stress. Another contributing outcome derived from the TGN trafficking brake likely involves an altered metabolism of ceramide and its derivatives, which is supported by a significant impact by SG on transport of ceramide and synthesis of its derivatives in post-Golgi organelles, whose intracellular accumulation induces apoptosis with multiple but poorly defined mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Bao

Zheng

Sugi

et al. 2015

Cancer Biology & Therapy

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Abbreviations: SA-J schweinfurthin A-J; TGN trans-Golgi-network; PTEN phosphatase and tensin homolog; DLBCL diffuse large B cell lymphoma; mTOR mammalian target of rapamycin; PDK1 phosphoinositide-dependent kinase 1; PIP3 phosphatidylinositol (3,4,5)-triphosphate; WGA wheat germ agglutinin; ConA concanavalin; MAA Maackia amurensis agglutinin; PNA peanut agglutinin; ORPs oxysterol-binding protein related family proteins Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golginetwork trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTENdeficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/ AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Bao

Zheng

Sugi

et al. 2015

Cancer Biology & Therapy

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“…The mechanism of ceramide-induced cell death through apoptosis is well established (12), inducing apoptosis through extrinsic and intrinsic pathways (13). The extrinsic apoptosis pathway is often triggered by the activation of tumor necrosis factor receptors, whereas the intrinsic pathway is initiated by mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Jin

Zheng

Xin

et al. 2014

Molecular Medicine Reports

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Abstract. Ceramide is a bioactive lipid which functions as a tumor suppressor, mediating processes such as apoptosis, growth arrest, senescence and differentiation. The effects of ceramide in ovarian cancers have not been well established. The objective of the present study was to investigate the effects of C2-ceramide treatment in A2780 ovarian cancer cells and its possible molecular mechanism. C2-ceramide-induced proliferation inhibition was analyzed using an MTT assay and Trypan blue test. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling were used to identify the induction of apoptosis. Transmission electron microscopy was used to confirm the formation of autophagosomes. Quantitative polymerase chain reaction was performed to analyze the messenger RNA expression of the autophagy and cell death associated genes and western blotting was used to analyze the protein expression of beclin 1, LC3, Akt, forkhead box O3 (FOXO3) and adenosine monophosphate-activated protein kinase in ovarian cancer cells. It was found that C2-ceramide inhibited A2780 cell proliferation in a time-and dose-dependent manner and C2-ceremide induced A2780 cell apoptosis and autophagy. However, C2-ceramide-induced autophagy did not result in cell death, but instead protected ovarian cancer cells from apoptosis. Akt inhibition and FOXO3 activation were implicated in C2-ceramide-treated ovarian cancer cells. Furthermore, FOXO3 target genes, which were associated with autophagy (MAP1LC3, GABARAP and GABARAPL1) and cell death (BNIP3, BNIP3L, BIM and PUMA), were upregulated. The present study has shown that C2-ceramide induced apoptosis and autophagy in ovarian cancer cells. FOXO3 transcription was upregulated, which may contribute to C2-ceramide-induced apoptosis and autophagy.

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“…The upregulation of rafts and caveolae, including that of the glucosphingolipid-enriched constituents of microdomains, represents another multidrug resistance (MDR) mechanism (11). Ceramide, as a second messenger of apoptosis, participates in cell death signaling, autophagy, and cellcycle arrest, and defects in ceramide generation and metabolism in cancer cells contribute to resistance to chemotherapy (12,13).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

Roh

Kim

Park

et al. 2015

Molecular Cancer Therapeutics

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Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or D,L-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P ¼ 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacologic inhibition of GCS induced accumulation of increased ceramide levels. GCS inhibition increased cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in cisplatin-resistant HNC.

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Ceramide-orchestrated signalling in cancer cells

Cited by 884 publications

References 197 publications

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

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