Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Yoon, Changhwan; Kim, Minjung; Park, Moon-Taek; Byun, Joo‐Yun; Choi, Young-Hyun; Yoo, Hwan‐Soo; Lee, Young Moo; Hyun, Jin‐Won; Lee, Su‐Jae

doi:10.1158/1541-7786.mcr-08-0069

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…These results clearly suggest that induction of senescence is a major response of the DKO cells. Interestingly, the β-galactosidase staining correlated best with the levels of sphingosine (Figure 4a), which has previously been associated with senescence pathways (Chao et al , 1992; Debacq-Chainiaux et al , 2010; Yoon et al , 2009). Collectively, these results suggest that by correcting ceramide and S1P levels, and possibly increasing sphingosine, knockout of SK1 rectifies the expression of cell cycle inhibitors and induces a strong cellular senescence response to prevent tumor development in p53 KO tissues.…”

Section: Resultssupporting

confidence: 58%

Defining a role for sphingosine kinase 1 in p53-dependent tumors

et al. 2011

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p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers. Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function. Bioactive sphingolipids have recently emerged as important regulators of proliferative, apoptotic and senescent cellular processes. In this study, we demonstrate that the enzyme sphingosine kinase 1 (SK1), a critical enzyme in the regulation of the key bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), serves as a key downstream target for p53 action. Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased. Importantly, deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by ~30%. Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice. The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence. Thus, targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer.

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Section: Resultssupporting

confidence: 58%

Defining a role for sphingosine kinase 1 in p53-dependent tumors

et al. 2011

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“…To further examine how DDX3 regulates camptothecin-induced apoptosis differently in cells with functional wild-type and mutant p53, p38 activation was examined because the p38 and p53 signaling pathways can mutually regulate each other in response to DNA damage (26) and the p38 pathway has been reported to be involved in the extrinsic apoptotic pathway where DDX3 is known to be regulatory (27). Following camptothecin treatment, DDX3 knockdown attenuated the activation of p38 in MCF-7 cells with active p53 (Figure 2A), but enhanced p38 activation in HeLa cells with nonfunctional p53 (Figure 2B), as determined by immunoblotting the active phosphorylated level of p38.…”

Section: Resultsmentioning

confidence: 99%

DDX3 regulates DNA damage-induced apoptosis and p53 stabilization

Sun

Zhou

Jonasch

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The DEAD box protein family member DDX3 was previously identified as an inhibitor of death receptor-mediated extrinsic apoptotic signaling. However, there had been no studies of the role of DDX3 in regulating the other major type of apoptosis, intrinsic apoptotic signaling, which was examined here. Intrinsic apoptosis was induced in MCF-7 cells by treatment with staurosporine, a general kinase inhibitor, thapsigargin, which induces endoplasmic reticulum (ER) stress, and camptothecin, which causes DNA damage. Each of these treatments caused time-dependent activation of caspase-7, the predominant executioner caspase in these cells. Depletion of DDX3 using shRNA did not alter apoptotic responses to staurosporine or thapsigargin. However, caspase-7 activation induced by camptothecin was regulated by DDX3 in a manner dependent on the functional status of p53. Depletion of DDX3 abrogated camptothecin-induced caspase-7 activation in MCF-7 cells expressing functional wild-type p53, but oppositely potentiated camptothecin-mediated caspase activation in cells expressing mutant or non-functional p53, which was accompanied by increased activation of the extrinsic apoptotic signaling initiator caspase-8. In MCF-7 cells, depletion of DDX3 reduced by more than 50% camptothecin-induced p53 accumulation, and this effect was blocked by inhibition of the proteasome with MG132, indicating that DDX3 regulates p53 not at expression level but rather its stabilization after DNA damage. Co-immunoprecipitation experiments demonstrated that DDX3 associates with p53, and overexpression of DDX3 was sufficient to double the accumulation of p53 in the nucleus after DNA damage. Thus, DDX3 associates with p53, increases p53 accumulation, and positively regulates camptothecin-induced apoptotic signaling in cells expressing functional wild-type p53, whereas in cells expressing mutant or non-functional p53 DDX3 inhibits activation of the extrinsic apoptotic pathway to reduce caspase activation. These results demonstrate that DDX3 not only regulates extrinsic apoptotic signaling, as previously reported, but also selectively regulates intrinsic apoptotic signaling following DNA damage.

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“…S1P is known to exert some of its mitogenic effects through the activation of both extracellular signal-regulated kinase (ERK), a prosurvival antiapoptotic MAPK, and the phosphoinositide 3-kinase (PI3K)/AKT prosurvival pathway (Wu et al, 1995;Bonnaud et al, 2010). Sphingosine and ceramide, on the other hand, are believed to induce cell death via activation of proapoptotic MAPKs, such as JNK and p38 mitogen-activated protein kinase (p38) (Westwick et al, 1995;Verheij et al, 1996;Jarvis et al, 1997;Yoon et al, 2009). Based on these previous studies, we examined the effect of inhibiting MAPK and PI3K/AKT signaling on SKI-178-induced cell death.…”

Section: Mechanism Of Action Of Ski-178mentioning

confidence: 99%

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

Dick

Hengst

Fox

et al. 2015

J Pharmacol Exp Ther

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We previously developed ethylidene]-3-(4-methoxxyphenyl)-1H-pyrazole-5-carbohydrazide) as a novel sphingosine kinase-1 (SphK1) selective inhibitor and, herein, sought to determine the mechanism-of-action of SKI-178-induced cell death. Using human acute myeloid leukemia (AML) cell lines as a model, we present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. Further examination of the mechanism of action of SKI-178 implicated c-Jun NH 2 -terminal kinase (JNK) and cyclin-dependent protein kinase 1 (CDK1) as critical factors required for SKI-178-induced apoptosis. In cell cycle synchronized human AML cell lines, we demonstrate that entry into mitosis is required for apoptotic induction by SKI-178 and that CDK1, not JNK, is required for SKI-178-induced apoptosis. We further demonstrate that the sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the prosurvival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multidrug resistance mediated by multidrug-resistant protein1 and/or prosurvival Bcl-2 family member overexpression did not affect the sensitivity of AML cells to SKI-178. Taken together, these findings highlight the therapeutic potential of SKI-178 targeting SphK1 as a novel therapeutic agent for the treatment of AML, including multidrug-resistant/recurrent AML subtypes.

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Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine

Cited by 24 publications

References 34 publications

Defining a role for sphingosine kinase 1 in p53-dependent tumors

Defining a role for sphingosine kinase 1 in p53-dependent tumors

DDX3 regulates DNA damage-induced apoptosis and p53 stabilization

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

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