Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells

Colombaioni, Laura; Frago, Laura M.; Varela-Nieto, Isabel; Pesi, Rossana; Garcia‐Gil, Mercedes

doi:10.1016/s0197-0186(01)00090-0

Cited by 43 publications

(29 citation statements)

References 45 publications

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“…P2X7 and Ca 2+ pathways are known to stimulate the exocytic release of nucleotides in other cell lines [20,21] and may act through VNUT secretory pathways [36]. Nutrient deprivation is also known to increase intracellular Ca 2+ [37], which may suggest that serum and glucose deprivation stimulate a Ca 2+ -dependent exocytic release of ADP. ADP release may also be facilitated by membrane channels, i.e., connexin hemichannels and pannexin, as described for ATP [38] or through membrane ATPases, such as F 1 -ATPase and ABC transporters [39].…”

Section: Discussionmentioning

confidence: 99%

P2X receptors regulate adenosine diphosphate release from hepatic cells

Chatterjee

Sparks

2014

Purinergic Signalling

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Extracellular nucleotides act as paracrine regulators of cellular signaling and metabolic pathways. Adenosine polyphosphate (adenosine triphosphate (ATP) and adenosine diphosphate (ADP)) release and metabolism by human hepatic carcinoma cells was therefore evaluated. Hepatic cells maintain static nanomolar concentrations of extracellular ATP and ADP levels until stress or nutrient deprivation stimulates a rapid burst of nucleotide release. Reducing the levels of media serum or glucose has no effect on ATP levels, but stimulates ADP release by up to 10-fold. Extracellular ADP is then metabolized or degraded and media ADP levels fall to basal levels within 2-4 h. Nucleotide release from hepatic cells is stimulated by the Ca 2+ ionophore, ionomycin, and by the P2 receptor agonist, 2′3′-O-(4-benzoyl-benzoyl)-adenosine 5′-triphosphate (BzATP). Ionomycin (10 μM) has a minimal effect on ATP release, but doubles media ADP levels at 5 min. In contrast, BzATP (10-100 μM) increases both ATP and ADP levels by over 100-fold at 5 min. Ion channel purinergic receptor P2X7 and P2X4 gene silencing with small interference RNA (siRNA) and treatment with the P2X inhibitor, A438079 (100 μM), decrease ADP release from hepatic cells, but have no effect on ATP. P2X inhibitors and siRNA have no effect on BzATP-stimulated nucleotide release. ADP release from human hepatic carcinoma cells is therefore regulated by P2X receptors and intracellular Ca 2+ levels. Extracellular ADP levels increase as a consequence of a cellular stress response resulting from serum or glucose deprivation.

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Section: Discussionmentioning

confidence: 99%

P2X receptors regulate adenosine diphosphate release from hepatic cells

Chatterjee

Sparks

2014

Purinergic Signalling

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“…In addition, numerous studies have depicted ceramides to be bioactive lipids that mediate various cellular processes, such as cell growth arrest, differentiation, and apoptosis (Reviewed in [14,17]). Studies from various laboratories indicate that cellular ceramides are increased in mammalian cells challenged with various stressful stimuli, such as pro-apoptotic cytokines (TNF-α [18], IL-1β [19], FAS ligand, and interferon γ [20]), cancer chemotherapeutic agents (etoposide and doxorubicin) [21], UV [22] and ionizing-irradiation [23], vitamins or derivatives (vitamin D [24,25] and retinoic acid [26]), and serum-deprivation [27]. Blocking increases in ceramide inhibits cell-growth arrest and/or apoptosis in response to these stressful stimuli.…”

Section: Role Of Ceramide In Cellular Responsesmentioning

confidence: 99%

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Mao

Obeid

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

349

325

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“…These results suggest that ACER3 knockdown does not induce apoptosis of HeLa cells under normal culture conditions. Because ceramides have been shown to mediate cell apoptosis in response to various stress stimuli, we determined whether ACER3 knockdown had any effect on cell apoptosis in response to a stimulus that induces the generation of ceramides, such as serum deprivation (36). HeLa cells transfected with different siRNAs were subjected to serum deprivation.…”

Section: Acer3 Down-regulation Inhibits Apoptosis In Response Tomentioning

confidence: 99%

Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis

Sun

et al. 2010

Journal of Biological Chemistry

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Ceramides with different fatty acyl chains may vary in their physiological or pathological roles; however, it remains unclear how cellular levels of individual ceramide species are regulated. Here, we demonstrate that our previously cloned human alkaline ceramidase 3 (ACER3) specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain (ULC) ceramides. In vitro, ACER3 only hydrolyzed C 18:1 -, C 20:1 -, C 20:4 -ceramides, dihydroceramides, and phytoceramides. In cells, ACER3 overexpression decreased C 18:1 -and C 20:1 -ceramides and dihydroceramides, whereas ACER3 knockdown by RNA interference had the opposite effect, suggesting that ACER3 controls the catabolism of ULC ceramides and dihydroceramides. ACER3 knockdown inhibited cell proliferation and up-regulated the cyclin-dependent kinase inhibitor p21 CIP1/WAF1 . Blocking p21 CIP1/WAF1 up-regulation attenuated the inhibitory effect of ACER3 knockdown on cell proliferation, suggesting that ACER3 knockdown inhibits cell proliferation because of p21 CIP1/WAF1 up-regulation. ACER3 knockdown inhibited cell apoptosis in response to serum deprivation. ACER3 knockdown up-regulated the expression of the alkaline ceramidase 2 (ACER2), and the ACER2 up-regulation decreased non-ULC ceramide species while increasing both sphingosine and its phosphate. Collectively, these data suggest that ACER3 catalyzes the hydrolysis of ULC ceramides and dihydroceramides and that ACER3 coordinates with ACER2 to regulate cell proliferation and survival.Ceramidases catalyze the hydrolysis of ceramides to form free fatty acids and sphingosine (SPH) 3 (1), and as such they are important intermediates of complex sphingolipids that play an important role in the integrity and function of cell membranes. Ceramides also act as bioactive molecules to mediate various cellular responses such as cell growth arrest, differentiation, and apoptosis in response to a variety of stress stimuli, including the cytokine tumor necrosis factor-␣ (2), cancer chemotherapeutic agents (3), UV (4), and ionizing radiation (5). Similar to ceramides, SPH also potently induces cell growth arrest, differentiation, or apoptosis (6, 7). SPH is phosphorylated by sphingosine kinases to generate sphingosine 1-phosphate (S1P) (8, 9). In contrast to ceramides and SPH, S1P mainly promotes cell proliferation and survival (10). Therefore, ceramidases may play an important role in regulating the levels of ceramides, SPH, and S1P as well as cellular responses mediated by these bioactive lipids.Ceramidases, according to their pH optima for in vitro activity, are classified into acid, neutral, and alkaline types (1, 11). Five human ceramidases encoded by five distinct genes have been identified as follows: the acid ceramidase (ASAH1) (12); neutral ceramidase (ASAH2) (13); alkaline ceramidase 1 (ACER1/ASAH3 (14); alkaline ceramidase 2 (ACER2/ASAH3L) (15); and alkaline ceramidase 3 (ACER3/ APHC/PHCA) (16).Ceramidases have different cellular localizations and substrate specificities. AS...

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Serum deprivation increases ceramide levels and induces apoptosis in undifferentiated HN9.10e cells

Cited by 43 publications

References 45 publications

P2X receptors regulate adenosine diphosphate release from hepatic cells

P2X receptors regulate adenosine diphosphate release from hepatic cells

Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate

Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis

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