Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis

Niaudet, Colin; Bonnaud, Stéphanie; Guillonneau, Maëva; Gouard, Sébastien; Gaugler, Marie‐Hélène; Dutoit, Soizic; Ripoche, Natacha; Dubois, Nolwenn; Trichet, Valérie; Corre, Isabelle; Pâris, François

doi:10.1016/j.cellsig.2017.02.001

Cited by 45 publications

(49 citation statements)

References 67 publications

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“…In eukaryotic cells, there are more than a dozen signaling pathways in MAPK involved in cell growth, differentiation, proliferation, and apoptosis. However, the main signaling pathways that have been identified include the ERK, JNK, and P38 pathways, of which the ERK transduction pathway is the main pathway that transmits extracellular signals to the nucleus, playing a major regulatory role in the process of cell proliferation, differentiation, and apoptosis . ERK1/2, an extracellular regulated protein kinase, is mainly activated via phosphorylation by external stimulation, and is a key signaling molecule that determines cell proliferation and differentiation or participates in cell apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Jiang

Zhou

et al. 2019

Thoracic Cancer

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Background Chronic inflammation plays a significant role in the occurrence and development of non‐small cell lung cancer (NSCLC). Hydroxysafflor yellow A (HSYA), a chemical compound of the yellow color pigments extracted from the safflower, has been widely used in clinical treatment with positive antioxidation, anti‐inflammation, and antitumor effects. However, the role and underlying mechanisms of HYSA on development and progress in inflammation‐mediated NSCLC are unknown. Methods Cell counting kit‐8, colony formation, EdU, cell apoptosis, wound healing, Transwell migration and invasion, and enzyme‐linked immunosorbent assays; flow cytometry; and Western blotting were conducted using human NSCLC cell lines A549 and H1299. Results Lipopolysaccharide (LPS) significantly promoted the proliferation and enhanced colony formation of A549 and H1299 cells, while HYSA notably reversed the effects of LPS. HYSA induced apoptosis of LPS‐mediated A549 and H1299 cells in a dose dependent manner; and remarkably suppressed migration, invasion, and epithelial–mesenchymal transition (EMT), significantly regulated production of LPS‐induced inflammation cytokines, and downregulated protein expression of PI3K/Akt/mTOR and ERK/MAPK signaling pathways in LPS‐induced A549 and H1299 cells. Furthermore, PI3K (LY294002) and ERK (SCH772984) inhibitors remarkably inhibited proliferation, migration, invasion, and EMT, and induced apoptosis in LPS‐mediated A549 and H1299 cells. These effects were even more obvious in the presence of HYSA and LY294002 or SCH772984 compared to those of either agent alone. Conclusion HYSA suppressed LPS‐mediated proliferation, migration, invasion, and EMT in A549 and H1299 cells by inhibiting the PI3K/Akt/mTOR and ERK/MAPK signaling pathways, indicating that HYSA may be a potential candidate to treat inflammation‐mediated NSCLC.

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Section: Discussionmentioning

confidence: 99%

Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Jiang

Zhou

et al. 2019

Thoracic Cancer

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“…Endothelial CAV1 deficiency increased the RT-induced activation of ASMase leading to increased ceramide generation EC apoptosis was shown to depend on the early generation of ceramide 25,27,36 . Moreover, ECs with reduced CAV1 expression levels were more apoptosis-prone and thus more sensitive to IR 19 .…”

Section: Resultsmentioning

confidence: 96%

“…RT-induced p38 activation in EC even reduced the survival protein AKT/PKB (protein kinase B), thereby promoting pro-apoptotic signaling 23,24 . RT-induced p38 pathway-dependent EC apoptosis was further linked to ASMase/ceramide signaling and plasma membrane reorganization 25 . ECs were characterized by high levels of ASMase expression that may account for the increased vulnerability of the endothelium to radiation-induced apoptosis 26,27 .…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor–stroma interactions

et al. 2020

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The integral membrane protein caveolin-1 (CAV1) plays a central role in radioresistance-mediating tumor-stroma interactions of advanced prostate cancer (PCa). Among the tumor-stroma, endothelial cells (EC) evolved as critical determinants of the radiation response. CAV1 deficiency in angiogenic EC was already shown to account for increased apoptosis rates of irradiated EC. This study explores the potential impact of differential CAV1 levels in EC on the acid sphingomyelinase (ASMase)/ceramide pathway as a key player in the regulation of EC apoptosis upon irradiation and cancer cell radioresistance. Enhanced apoptosis sensitivity of CAV1-deficient EC was associated with increased ASMase activity, ceramide generation, formation of large lipid platforms, and finally an altered p38 mitogen-activated protein kinase (MAPK)/heat-shock protein 27 (HSP27)/AKT (protein kinase B, PKB) signaling. CAV1-deficient EC increased the growth delay of LNCaP and PC3 PCa cells upon radiation treatment in direct 3D spheroid co-cultures. Exogenous C6 and C16 ceramide treatment in parallel increased the growth delay of PCa spheroids and induced PCa cell apoptosis. Analysis of the respective ceramide species in PCa cells with increased CAV1 levels like those typically found in radioresistant advanced prostate tumors further revealed an upregulation of unsaturated C24:1 ceramide that might scavenge the effects of EC-derived apoptosis-inducing C16 ceramide. Higher ASMase as well as ceramide levels could be confirmed by immunohistochemistry in human advanced prostate cancer specimen bearing characteristic CAV1 tumor-stroma alterations. Conclusively, CAV1 critically regulates the generation of ceramide-dependent (re-) organization of the plasma membrane that in turn affects the radiation response of EC and adjacent PCa cells. Understanding the CAV1-dependent crosstalk between tumor cells and the host-derived tumor microvasculature and its impact on radiosensitivity may allow to define a rational strategy for overcoming tumor radiation resistance improving clinical outcomes by targeting CAV1.

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“…Down-regulation of ASM leads to a blunted p38/ MAPK response (34,35), and in ASM KD cells, this effect is reflected in a greater susceptibility to toxin-induced membrane damage, less efficient repair, less blebbing, and diminished viability. Moreover, the inhibition of ASM has been shown to reduce the uptake of membrane lesions by endocytosis (22).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we monitored the p38/MAPK signaling pathway, which plays a central role in the response to cellular injury and is implicated in signaling both through ASM and NSM-2 (15,(32)(33)(34)(35). Activation of p38/MAPK has been associated with improved survival of bacterial toxin-related injury (32,33).…”

mentioning

confidence: 99%

Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins

et al. 2018

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Bacterial pore‐forming toxins compromise plasmalemmal integrity, leading to Ca2+ influx, leakage of the cytoplasm, and cell death. Such lesions can be repaired by microvesicular shedding or by the endocytic uptake of the injured membrane sites. Cells have at their disposal an entire toolbox of repair proteins for the identification and elimination of membrane lesions. Sphingomyelinases catalyze the breakdown of sphingomyelin into ceramide and phosphocholine. Sphingomyelin is predominantly localized in the outer leaflet, where it is hydrolyzed by acid sphingomyelinase (ASM) after lysosomal fusion with the plasma membrane. The magnesium‐dependent neutral sphingomyelinase (NSM)‐2 is found at the inner leaflet of the plasmalemma. Because either sphingomyelinase has been ascribed a role in the cellular stress response, we investigated their role in plasma membrane repair and cellular survival after treatment with the pore‐forming toxins listeriolysin O (LLO) or pneumolysin (PLY). Jurkat T cells, in which ASM or NSM‐2 was down‐regulated [ASM knockdown (KD) or NSM‐2 KD cells], showed inverse reactions to toxin‐induced membrane damage: ASM KD cells displayed reduced toxin resistance, decreased viability, and defects in membrane repair. In contrast, the down‐regulation of NSM‐2 led to an increase in viability and enhanced plasmalemmal repair. Yet, in addition to the increased plasmalemmal repair, the enhanced toxin resistance of NSM‐2 KD cells also appeared to be dependent on the activation of p38/MAPK, which was constitutively activated, whereas in ASM KD cells, the p38/MAPK activation was constitutively blunted.—Schoenauer, R., Larpin, Y., Babiychuk, E. B., Drücker, P., Babiychuk, V. S., Avota, E., Schneider‐Schaulies, S., Schumacher, F., Kleuser, B., Köffel, R., Draeger, A. Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins. FASEB J. 33, 275–285 (2019). http://www.fasebj.org

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Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis

Cited by 45 publications

References 67 publications

Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor–stroma interactions

Down‐regulation of acid sphingomyelinase and neutral sphingomyelinase‐2 inversely determines the cellular resistance to plasmalemmal injury by pore‐forming toxins

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