Dihydroceramide delays cell cycle G1/S transition via activation of ER stress and induction of autophagy

Gagliostro, Vincenzo; Casas, Josefina; Caretti, Anna; Abad, José Luı́s; Tagliavacca, Luigina; Ghidoni, Riccardo; Fabriás, Gemma; Signorelli, Paola

doi:10.1016/j.biocel.2012.08.025

Cited by 70 publications

(68 citation statements)

References 48 publications

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“…First, the SK1 specifi c inhibitor, PF543, did not affect HGC 27 cell proliferation at 8 and 24 h, although it avoided S1P production with no remarkable changes in other sphingolipid species. Second, the effect of dhCers at slowing or arresting the cell cycle with accumulation of cells in the G0/G1 phase is welldocumented ( 35,(83)(84)(85). Therefore, we suggest that the effect of SKI II on the cell cycle may be due to the accumulation of dhCer resulting from its Des1 inhibitory activity.…”

Section: Discussionmentioning

confidence: 79%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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proapoptotic sphingosine (So) and ceramide (Cer). Thus, as central enzymes in modulating the Cer/S1P balance, SKs are attractive targets for cancer therapy ( 1 ). Two SKs exist in humans, SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence that proves its role in promoting cell survival, proliferation, and neoplastic transformation ( 2-5 ). SK1 is also elevated in many human cancers, which appears to contribute to carcinogenesis, chemotherapeutic resistance, and poor patient outcome. SK2, however, has not been as well-characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumors ( 6 ).The potential of SKs as therapeutic targets has boosted the development of small molecule inhibitors ( 4,(7)(8)(9)(10)(11)(12)(13)(14). A detailed characterization of their pharmacology, particularly their selectivity against human SK1 and SK2, has been published ( 15 ). The fi rst known SK inhibitors were long chain base analogs such as N , N -dimethyl-D-erythro-sphingosine (DMS) ( 16,17 ) and L-threo-dihydrosphingosine (safi ngol) ( 18-21 ). While DMS inhibits both SK1 and SK2 by (SGR 2009(SGR 1072, and the Fundació la Marató de TV3 (112130 and 112132 Abbreviations: CB5R, NADH-cytochrome b5 reductase; C16dhCer, N -hexadecanoyldihydrosphingosine ; CDH, ceramide dihexoside (lactosylceramide); Cer, ceramide; CerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphingosine; CMH, ceramide monohexoside (glucosyl and galactosylceramide); Des1, dihydroceramide desaturase; dhCDH, dihydroceramide dihexoside (lactosyldihydroceramide); dhCer, dihydroceramide; dhCerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-dihydrosphingosine; dhSM, dihydrosphingomyelin; DMS, N , N -dimethyl-D-erythro-sphingosine; FAD, fl avin adenine dinucleotide; LC3, microtubule-associated protein 1-light chain 3; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NBD, 4-nitro-2,1,3-benzoxadiazole; PDB, Protein Data Bank; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor; So, sphingosine; TBST, TBS with 0.1% Tween 20; UPLC, ultraperformance LC . This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-22444), the Generalitat de Catalunya

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Section: Discussionmentioning

confidence: 79%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

Self Cite

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“…When Merrill's group discovered that fenretinide inhibited Des1, they also found that both it and dihydrosphingolipids induced autophagy (43). Subsequent studies demonstrated that other Des1 inhibitors recapitulated this effect (36,46,47). This is particularly interesting to those of us studying metabolic diseases, as autophagy is a proposed mechanism for clearing excess lipid in the liver and thus could serve as a means of ameliorating hepatic steatosis, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) (48)(49)(50).…”

Section: Discussionmentioning

confidence: 92%

Ablation of Dihydroceramide Desaturase 1, a Therapeutic Target for the Treatment of Metabolic Diseases, Simultaneously Stimulates Anabolic and Catabolic Signaling

Siddique

Liu

Wang

et al. 2013

Molecular and Cellular Biology

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The lipotoxicity hypothesis posits that obesity predisposes individuals to metabolic diseases because the oversupply of lipids to tissues not suited for fat storage leads to the accumulation of fat-derived molecules that impair tissue function. Means of combating this have been to stimulate anabolic processes to promote lipid storage or to promote catabolic ones to drive fat degradation. Herein, we demonstrate that ablating dihydroceramide desaturase 1 (Des1), an enzyme that produces ceramides, leads to the simultaneous activation of both anabolic and catabolic signaling pathways. In cells lacking Des1, the most common sphingolipids were replaced with dihydro forms lacking the double bond inserted by Des1. These cells exhibited a remarkably strong activation of the antiapoptotic and anabolic signaling pathway regulated by Akt/protein kinase B (PKB), were resistant to apoptosis, and were considerably larger than their wild-type counterparts. Paradoxically, Des1؊/؊ cells exhibited high levels of autophagy. Mechanistic studies revealed that this resulted from impaired ATP synthesis due in part to decreased expression and activity of several complexes of the electron transport chain, particularly complex IV, leading to activation of AMP-activated protein kinase and its induction of the autophagosome. Thus, Des1 ablation enhanced starvation responses but dissociated them from the anabolic, prosurvival, and antiautophagic Akt/PKB pathways.

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“…(81) also conducted studies using a dihydroceramide desaturase inhibitor, XM462, which induces a transient early increase in dihydroceramides and other sph-ingolipids composed of a dihydroceramide backbone. This dihydroceramide accumulation was also associated with decreased proliferation rates and a delayed G 1 /S transition (19).…”

Section: Cell Proliferationmentioning

confidence: 94%

“…Subsequent studies involving other pharmacological inhibitors to reduce DES1 activity (19,20) or using fibroblasts from knock-out mice lacking the first exon of the Des1 gene (21) further support a role for these unique sphingolipids in autophagy induction. In all of these studies, inhibition of DES1 increased sensitivity to autophagic stimuli.…”

Section: Autophagymentioning

confidence: 99%

Dihydroceramides: From Bit Players to Lead Actors

Siddique¹,

Chaurasia

et al. 2015

Journal of Biological Chemistry

120

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Sphingolipid synthesis involves a highly conserved biosynthetic pathway that produces fundamental precursors of complex sphingolipids. The final reaction involves the insertion of a double bond into dihydroceramides to generate the more abundant ceramides, which are converted to sphingomyelins and glucosylceramides/gangliosides by the addition of polar head groups. Although ceramides have long been known to mediate cellular stress responses, the dihydroceramides that are transiently produced during de novo sphingolipid synthesis were deemed inert. Evidence published in the last few years suggests that these dihydroceramides accumulate to a far greater extent in tissues than previously thought. Moreover, they have biological functions that are distinct and non-overlapping with those of the more prevalent ceramides. Roles are being uncovered in autophagy, hypoxia, and cellular proliferation, and the lipids are now implicated in the etiology, treatment, and/or diagnosis of diabetes, cancer, ischemia/ reperfusion injury, and neurodegenerative diseases. This minireview summarizes recent findings on this emerging class of bioactive lipids.

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Dihydroceramide delays cell cycle G1/S transition via activation of ER stress and induction of autophagy

Cited by 70 publications

References 48 publications

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Ablation of Dihydroceramide Desaturase 1, a Therapeutic Target for the Treatment of Metabolic Diseases, Simultaneously Stimulates Anabolic and Catabolic Signaling

Dihydroceramides: From Bit Players to Lead Actors

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