ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis

Kelkel, Mareike; Cerella, Claudia; Mack, Fabienne; Schneider, Thomas; Jacob, Claus; Schumacher, Marc; Dicato, Mario; Diederich, Marc

doi:10.1093/carcin/bgs240

Cited by 68 publications

(39 citation statements)

References 54 publications

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“…3B). Numerous studies have implicated JNK in the phosphorylation of Bcl-2 at Ser70 in response to agents that induce mitotic arrest and subsequent apoptotic cell death (Fan et al, 2000;Kelkel et al, 2012). However, a recent study provided evidence that a known JNK inhibitor, SP600125, also inhibits CDK1 (Kim et al, 2010).…”

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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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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“…Indeed, diallyl tetrasulfide (10 μM) induces an accumulation of cells in early mitosis (G2/M phase), followed by the activation of a caspase-dependent apoptotic pathway [65]. Diallyl tetrasulfide-induced apoptosis seems to be independent of ROS, and tubulin depolymerization represents its main cellular target [66]. The antiproliferative effects exerted by DADS (560 and 1120 μM) lead to apoptosis through its ability of binding tubulin and disrupting the microtubule assembly.…”

Section: Microtubule Alterations and Calcium Homeostasis Changesmentioning

confidence: 99%

Anticancer Mechanism of Sulfur-Containing Compounds

Gianni

Fimognari

2015

The Enzymes

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“…Of course, this requires that we continue making great efforts and study further mechanisms of JNK activation. After all, an elevated phosphorylation level of Bcl-2 has been observed following ABT-199 treatment, which could be regulated by JNK activation [38, 39]. …”

Section: Discussionmentioning

confidence: 99%

Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells

Zhang

Tan

et al. 2016

Oncotarget

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The regulation of Mcl-1 expression is necessary for the induction of cancer cell apoptosis by ABTs such as ABT-737, ABT-263 and ABT-199. However, the reduction in Mcl-1 expression is not sufficient for initiating cell death in hematopoietic cancer cells with high Bcl-xL expression. Here, we demonstrate that 2-deoxyglucose (2-DG) enhanced the effect of ABT-199 to induce cell apoptosis in hematologic malignancies with up-regulated Bcl-xL expression. Our study revealed that 2-DG could decrease glucose-dependent and Akt-independent Mcl-1 expression, which is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, the combination of 2-DG and ABT-199 triggered c-Jun NH2-terminal kinase (JNK) phosphorylation and subsequent Bcl-xL degradation, whereas 2-DG and ABT-199 alone had little effect on JNK activation. Therefore, the combination of 2-DG and ABT-199 initiated cell death through the reduction of Mcl-1 expression and JNK activation. Our study could provide a clinical theoretical basis for the use of ABT-199 in hematologic malignancies with excessive Bcl-xL expression.

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ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis

Cited by 68 publications

References 54 publications

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

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

Anticancer Mechanism of Sulfur-Containing Compounds

Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells

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