D,L-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (DL-PDMP) increases endoplasmic reticulum stress, autophagy and apoptosis accompanying ceramide accumulation via ceramide synthase 5 protein expression in A549 cells

Yamane, Mototeru; Miyazawa, Kenji; Moriya, Shota; Abe, Akihisa; Yamane, Sayoko

doi:10.1016/j.biochi.2011.04.016

Cited by 21 publications

(25 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unfortunately, our data indicate that inhibition of glucosylceramide synthesis exacerbates cisplatin-induced AKI, as a result of exacerbating cisplatininduced ceramide accumulation. Importantly, Yamane et al (74) showed that administration of PDMP (a glucosylceramide synthase inhibitor) to lung cancer cells induced ER stress, autophagy, and apoptosis as a result of PDMP-induced ceramide accumulations. The work done by Yamane et al (74) highlights the fact that, while drugs acting to increase ceramide levels may have the potential to sensitize cancer cells to cisplatin treatment, these drugs may further exacerbate cisplatin-induced AKI, as evidenced by the data presented in this report.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, Yamane et al (74) showed that administration of PDMP (a glucosylceramide synthase inhibitor) to lung cancer cells induced ER stress, autophagy, and apoptosis as a result of PDMP-induced ceramide accumulations. The work done by Yamane et al (74) highlights the fact that, while drugs acting to increase ceramide levels may have the potential to sensitize cancer cells to cisplatin treatment, these drugs may further exacerbate cisplatin-induced AKI, as evidenced by the data presented in this report. Thus, it may be beneficial when developing agents targeting sphingolipid metabolism, to target portions of the pathway that are either upstream or downstream of ceramide or to develop formulations that enable targeting drugs specifically to the tumor.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

Dupre

Doll

Shah

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

. Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury. J. Lipid Res. 2017. 58: 1439-1452. Supplementary key words ceramide • sphingolipids • apoptosis • inflammationAcute kidney injury (AKI) is a rapid decline in kidney function that occurs within hours to days of the initial kidney insult (1). The incidence of AKI is more than 5,000 cases per million per year for non-dialysis-requiring patients, while the incidence of AKI for dialysis-requiring patients is greater than 295 cases per million per year (1, 2). AKI complications are observed in 1-9% of hospital inpatients, with 40% of these patients being admitted to the intensive care unit due to AKI complications; more than 60% of patients in the intensive care unit have some sort of AKI episode during their stay, resulting in a 50-70% increased mortality rate (1,3,4). A common cause of AKI is nephrotoxic pharmacological agents, which account for 55-60% of hospital inpatient AKI cases (4). These agents include many antibiotics and anti-cancer chemotherapeutics. Abbreviations: AKI, acute kidney injury; aSMase, acid sphingomyelinase; BUN, blood urea nitrogen; CerS, ceramide synthase; CXCL1, chemokine (C-X-C motif) ligand 1; ER, endoplasmic reticulum; IL, interleukin; I/R, ischemia/reperfusion; KIM-1, kidney injury molecule-1; LTA, lectin from Tetragonolobus purpureus; MCP-1, monocyte chemotactic protein-1; PAS, periodic acid Schiff; PCNA, proliferating cell nuclear antigen; PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; SCr, serum creatinine; S1P, sphingosine 1-phosphate; TBST, TBS with 0.1% Tween 20; TLR4, toll-like receptor 4. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK093462 (L.J.S.); National Institutes of Health Grants P30 CA138313 (A.B., J.B.), P20RR017677 (A.B., J.B.), UH2NS092981 (J.S.), 1R01HD076004-04 (J.S.), GM097741 (L.M.O.), and PO1CA097132 (L.M.O.); and Veterans Affairs Merit Awards 1I01BX002021-04 (J.S.) and CAMM-011-13S (L.M.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

Dupre

Doll

Shah

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Some studies indicate that enhanced ceramide levels lead to increased autophagy [60–64], whereas there is evidence that elevated ceramides inhibit autophagy by cleaving Atg5 that is necessary for autophagy [65] or via inducing tubulin acetylation that inhibits autophagosome motility [66]. Data in the literature also suggest that particular ceramide synthase isoforms and/or dihydroceramide or ceramide species may differentially regulate autophagy and whether it is protective from cellular stress or leads to cell death [61–64,67–71]. Studies have also examined the role of ceramide metabolites in autophagy.…”

Section: Discussionmentioning

confidence: 99%

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Sundaram

Mather

Marimuthu

et al. 2016

Biochemical Journal

View full text Add to dashboard Cite

Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase−/−) were protected from 2DG/AA. Although nCDase−/− cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase−/− cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase−/− MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient-deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

show abstract

“…In A549 cells, active caspase 3 expression with C16:0-Cer accumulation in mitochondria was not detected by the blocking effect in the caspase 9 to caspase 3 process by survivin having an inhibitory effect on the activation of caspase 9 [5] , [6] . Therefore, endogenous C16:0-Cer accumulation in A549 cells would likely be related to a pathway (e.g., the pathway of necrotic cell death) distinct from the mitochondrial caspase-dependent pathway.…”

Section: Introductionmentioning

confidence: 89%

Visualization of ceramide channels in lysosomes following endogenous palmitoyl-ceramide accumulation as an initial step in the induction of necrosis

Yamane

Moriya

Kokuba

2017

Biochemistry and Biophysics Reports

Self Cite

View full text Add to dashboard Cite

In this study, we showed that the dual addition of glucosyl ceramide synthase and ceramidase inhibitors to A549 cell culture led to the possibility of ceramide channel formation via endogenous palmitoyl-ceramide accumulation with an increase in cholesterol contents in the lysosome membrane as an initial step prior to initiation of necrotic cell death. In addition, the dual addition led to black circular structures of 10–20 nm, interpreted as stain-filled cylindrical channels on transmission electron microscopy. The formation of palmitoyl-ceramide channels in the lysosome membrane causes the liberation of cathepsin B from lysosomes for necrotic cell death. On the other hand, necrotic cell death in the dual addition was not caused by oxidative stress or cathepsin B activity, and the cell death was free from the contribution of the translation of Bax protein to the lysosome membrane.

show abstract

D,L-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (DL-PDMP) increases endoplasmic reticulum stress, autophagy and apoptosis accompanying ceramide accumulation via ceramide synthase 5 protein expression in A549 cells

Cited by 21 publications

References 33 publications

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Visualization of ceramide channels in lysosomes following endogenous palmitoyl-ceramide accumulation as an initial step in the induction of necrosis

Contact Info

Product

Resources

About