C<sub>2</sub>‐ceramide mediates cerebellar granule cells apoptosis by activation of caspases‐2, ‐9, and ‐3

Miñano, Alfredo; Caballero-Benítez, Andrea; Lluch, Mónica; Morán, Julio; Rodríguez‐Álvarez, José

doi:10.1002/jnr.21633

Cited by 14 publications

(9 citation statements)

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“…Activation of these caspases has a pivotal role in promoting apoptosis (41). Cleavedcaspase 3 is the executor of apoptosis (42). Our results also showed that the levels of cleaved-caspase 9 and cleaved-caspase 3 were decreased after the MDHB treatment, indicating that MDHB can inhibit the activation of pro-caspase 9 and pro-caspase 3.…”

Section: Discussionsupporting

confidence: 60%

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

Zhou

Zhang

et al. 2014

J Pharmacol Sci

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Section: Discussionsupporting

confidence: 60%

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

Zhou

Zhang

et al. 2014

J Pharmacol Sci

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“…It is known that both stimuli induce apoptosis by activating the cascade of caspases and their substrates. 40 , 41 , 42 , 43 , 44 We demonstrated that overexpression and activation of SGK-1 reduced the cleavage of caspase-3 after C 2 -ceramide stimulus and inactivation of caspase-3 substrate (PARP-1), protecting against apoptosis. We showed, for the first time, a direct relationship between SGK-1 and caspase's cascade.…”

Section: Discussionmentioning

confidence: 85%

SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α

et al. 2015

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Ceramide regulates several different cellular responses including mechanisms leading to apoptosis. Serum- and glucocorticoid-inducible protein kinase (SGK)-1 is a serine threonine kinase, which activates survival pathways in response to stress stimuli. Recently, we demonstrated an anti-apoptotic role of SGK-1 in human umbilical endothelial cells treated with high glucose. In the present study, since ceramide induces apoptosis by multiple mechanisms in diabetes and its complication such as nephropathy, we aimed to investigate whether SGK-1 may protect even against apoptosis induced by ceramide in kidney cells. Human embryonic kidney (HEK)-293 cells stable transfected with SGK-1 wild type (SGK-1wt) and its dominant negative gene (SGK-1dn) have been used in this study. Apoptotic stimuli were induced by C2-ceramide and TNF-α to increase endogenous synthesis of ceramide. Upon activation with these stimuli, SGK-1wt transfected cells have a statistically significant reduction of apoptosis compared with SGK-1dn cells (P<0.001). This protection was dependent on activation of caspase-3 and Poly-ADP-ribose-polymerase-1 (PARP-1) cleavage. SGK-1 and AKT-1 two highly homologous kinases differently reacted to ceramide treatment, since SGK-1 increases in response to apoptotic stimulus while AKT-1 decreases. This enhancement of SGK-1 was dependent on p38-mitogen-activated-protein kinases (p38MAPK), cyclic-adenosine-monophosphate/protein kinase A (cAMP/PKA) and phosphoinositide-3-kinase (PI3K) pathways. Especially, by using selective LY294002 inhibitor, we demonstrated that the most involved pathway in the SGK-1 mediated process of protection was PI3K. Treatment with inhibitor of SGK-1 (GSK650394) significantly enhanced TNF-α-dependent apoptosis in HEK-293 cells overexpressing SGK-1wt. Caspase-3, -8 and -9 selective inhibitors confirmed that SGK-1 reduced the activation of caspase-dependent apoptosis, probably by both intrinsic and extrinsic pathways. In conclusion, we demonstrated that in kidney cells, overexpression of SGK-1 is protective against ceramide-induced apoptosis and the role of SGK-1 can be potentially explored as a therapeutic target in conditions like diabetes, where ceramide levels are increased.

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“…However, no previous report has considered the role of ceramide in this process. Only Miñano et al [24] demonstrated that the addition of exogenous C2-ceramide, a non-physiological short-chain ceramide, can induce caspase-2 cleavage, which is responsible for the triggering of late apoptosis. The new finding presented in this paper is the existence of a significant correlation between the increase in the amount of late ceramide in radioresistant SQ20B and U87MG cells, and the induction of delayed apoptosis after high and low LET-radiation.…”

Section: Discussionmentioning

confidence: 99%

p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation

et al. 2013

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BackgroundTo determine whether ceramide is responsible for the induction of p53-independent early or late apoptosis in response to high- and low-Linear-Energy-Transfer (LET) irradiation.MethodsFour cell lines displaying different radiosensitivities and p53-protein status were irradiated with photons or 33.4 or 184 keV/μm carbon ions. The kinetics of ceramide production was quantified by fluorescent microscopy or High-Performance-Liquid-Chromatogaphy and the sequence of events leading to apoptosis by flow cytometry.ResultsRegardless of the p53-status, both low and high-LET irradiation induced an early ceramide production in radiosensitive cells and late in the radioresistant. This production strongly correlated with the level of early apoptosis in radiosensitive cells and delayed apoptosis in the radioresistant ones, regardless of radiation quality, tumor type, radiosensitivity, or p53-status. Inhibition of caspase activity or ceramide production showed that, for both types of radiation, ceramide is essential for the initiation of early apoptosis in radiosensitive cells and late apoptosis following mitotic catastrophe in radioresistant cells.ConclusionsCeramide is a determining factor in the onset of early and late apoptosis after low and high-LET irradiation and is the mediator of the p53-independent-apoptotic pathway. We propose that ceramide is the molecular bridge between mitotic catastrophe and the commitment phase of delayed apoptosis in response to irradiation.

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C₂‐ceramide mediates cerebellar granule cells apoptosis by activation of caspases‐2, ‐9, and ‐3

Cited by 14 publications

References 47 publications

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α

p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation

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C2‐ceramide mediates cerebellar granule cells apoptosis by activation of caspases‐2, ‐9, and ‐3

Cited by 14 publications

References 47 publications

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

Neuroprotective Effects of Methyl 3,4-dihydroxybenzoate Against H2O2-Induced Apoptosis in RGC-5 Cells

SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α

p53-independent early and late apoptosis is mediated by ceramide after exposure of tumor cells to photon or carbon ion irradiation

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C₂‐ceramide mediates cerebellar granule cells apoptosis by activation of caspases‐2, ‐9, and ‐3