GSK-3β acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis

Lin, Chiou Feng; Chen, Chia Ling; Chiang, Chi Wu; Jan, Ming‐Shiou; Huang, Wei-Ching; Lin, Yee Shin

doi:10.1242/jcs.03473

Cited by 127 publications

(120 citation statements)

References 65 publications

(66 reference statements)

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“…Ceramide is indeed able, by directly promoting the recruitment into lipid raft of phosphatase and tensin homologue (43) and/or by indirectly activating ceramide-activated protein phosphatase 2A (43,44), to inhibit specifically this pathway, conducting to NF-κB inactivation and to decreased Bcl-xL expression. Conversely, both SphK1 and, indirectly, S1P by acting in an autocrine loop via its S1PR/Edg receptors are able to stimulate this same pathway (45,46).…”

Section: Discussionmentioning

confidence: 99%

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guillermet-Guibert

Davenne

Pchejetski

et al. 2009

Molecular Cancer Therapeutics

114

100

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Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/ S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.

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Section: Discussionmentioning

confidence: 99%

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guillermet-Guibert

Davenne

Pchejetski

et al. 2009

Molecular Cancer Therapeutics

114

100

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“…PP2A dephosphorylates and activates GSK-3β [27] while Akt can inactivate GSK-3β by phosphorylating GSK-3β at Ser9 [28] . Alternatively, PP2A can act upstream of Akt pathway to indirectly regulate GSK-3β signaling [15] . However, our results demonstrate that only Akt activation is involved in the inactivation of GSK-3β by ASA in PANC-1 cells, which takes place independently of PP2A pathway.…”

Section: Discussionmentioning

confidence: 99%

“…To further elucidate the signaling pathways that inactivate GSK-3β, we examined the effect of ASA on Akt and PP2A, which are both implicated in the regulation of GSK-3β activity [15] . In untreated PANC-1 cells, phosphorylated Akt at Ser437 is marginal.…”

Section: Asa Inhibits Gsk-3β Activation In Panc-1 Cellsmentioning

confidence: 99%

Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity

Zhu

et al. 2009

Acta Pharmacol Sin

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Aim: To investigate whether aspirin is able to augment gemcitabine-induced cytotoxicity in human pancreatic cancer cells. Methods: Two gemcitabine-insensitive human pancreatic cancer cell lines, PANC-1 and Capan-1, were used. Cells were treated with either aspirin or gemcitabine alone or both of them. Cell growth and apoptosis were determined by MTT assay, Annexin V or Hoechest 33258 staining. Cell cycle distribution was examined by flow cytometry. Western blot with specific phosphorylated protein antibodies was used to detect the activation of protein kinase. RT-PCR and Western blot were applied to assess the transcription and protein level for cyclin D1 and Bcl-2. Results: Aspirin alone significantly inhibits the proliferation of PANC-1 cells by causing cell cycle arrest at G 1 phase. Aspirin potentiates the anti-survival effect of gemcitabine as well as its pro-apoptotic effect in PANC-1 cells, although aspirin per se does not trigger apoptosis. Aspirin inhibits GSK-3β activation and suppresses the expression of its downstream gene products (cyclin D1 and Bcl-2), which are implicated in proliferation, survival and chemoresistance of pancreatic cancer. The effects of aspirin on Capan-1, were similar to that on PANC-1. Conclusion: Our results suggest that aspirin inhibits the proliferation of gemcitabine-resistant pancreatic cancer cells and augments the antisurvival effect of gemcitabine, probably by suppressing the activity of GSK-3β and its downstream gene products.

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“…We previously showed ceramide-induced apoptosis via GSK-3b activation in various types of cells (50). We further showed that ceramide induced dephosphorylation of GSK-3b at S9, which is the inhibitory phosphorylation site of GSK-3b, in HMEC-1 cells (Fig.…”

Section: The Activation Of Gsk-3b Is Involved In Regulation Of Ceramimentioning

confidence: 55%

“…In anti-DENV NS1 Abstimulated endothelial cells, aSMase effectively regulated GSK3b activation, suggesting an essential role for ceramide in this pathway. The proapoptotic effect of ceramide through a GSK-3b-regulated manner has been previously demonstrated (50). To further demonstrate the pathogenic role of GSK-3b, we investigated an in vivo model of anti-DENV NS1-induced endothelium injury in liver using GSK-3b inhibitor LiCl.…”

Section: Discussionmentioning

confidence: 91%

Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation

Chen

Lin

Wan

et al. 2013

The Journal of Immunology

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Immunopathogenetic mechanisms of dengue virus (DENV) infection are involved in hemorrhagic syndrome resulting from thrombocytopenia, coagulopathy, and vasculopathy. We have proposed a mechanism of molecular mimicry in which Abs against DENV nonstructural protein 1 (NS1) cross-react with human endothelial cells and cause NF-κB–regulated immune activation and NO-mediated apoptosis. However, the signaling pathway leading to NF-κB activation after the binding of anti-DENV NS1 Abs to endothelial cells is unresolved. In this study, we found that anti-DENV NS1 Abs caused the formation of lipid raftlike structures, and that disrupting lipid raft formation by methyl-β-cyclodextrin decreased NO production and apoptosis. Treatment with anti-DENV NS1 Abs elevated ceramide generation in lipid rafts. Pharmacological inhibition of acid sphingomyelinase (aSMase) decreased anti-DENV NS1 Ab-mediated ceramide and NO production, as well as apoptosis. Exogenous ceramide treatment induced biogenesis of inducible NO synthase (iNOS)/NO and apoptosis through an NF-κB–regulated manner. Furthermore, activation of glycogen synthase kinase-3β (GSK-3β) was required for ceramide-induced NF-κB activation and iNOS expression. Notably, anti-DENV NS1 Abs caused GSK-3β–mediated NF-κB activation and iNOS expression, which were regulated by aSMase. Moreover, pharmacological inhibition of GSK-3β reduced hepatic endothelial cell apoptosis in mice passively administered anti-DENV NS1 Abs. These results suggest that anti-DENV NS1 Abs bind to the endothelial cell membrane and cause NO production and apoptosis via a mechanism involving the aSMase/ceramide/GSK-3β/NF-κB/iNOS/NO signaling pathway.

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GSK-3β acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis

Cited by 127 publications

References 65 publications

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity

Anti–Dengue Virus Nonstructural Protein 1 Antibodies Cause NO-Mediated Endothelial Cell Apoptosis via Ceramide-Regulated Glycogen Synthase Kinase-3β and NF-κB Activation

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