Hematopoietic cytokines enhance Chk1-dependent G2/M checkpoint activation by etoposide through the Akt/GSK3 pathway to inhibit apoptosis

Jin, Zhen-Hua; Kurosu, Tetsuya; Yamaguchi, Mitsuko; Arai, Ayako; Miura, Osamu

doi:10.1038/sj.onc.1208408

Cited by 44 publications

(52 citation statements)

References 36 publications

(56 reference statements)

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“…7A), because inhibition of Chk1-mediated phosphorylation of cdc25C promotes dephosphorylation of cdc2 on tyrosine 15. 63 CML-BC cells treated with MMC displayed accu- mulation in S phase and in G 2 /M phase at 12 h and 24 h, respectively, after MMC treatment (Fig. 7B, boxes 3), consistent with activation of transient intra-S phase checkpoint followed by G 2 /M checkpoint.…”

Section: Atr-chk1 Axis Plays a Role In Resistance Of Bcr/abl-positivementioning

confidence: 69%

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Nieborowska‐Skorska

Stokłosa²,

Datta³

et al. 2006

Cell Cycle

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BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA doublestrand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (γ-H2AX). γ-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G 2 /M cell cycle phases after drug treatment. In conclusion, ATR -Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

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Section: Atr-chk1 Axis Plays a Role In Resistance Of Bcr/abl-positivementioning

confidence: 69%

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Nieborowska‐Skorska

Stokłosa²,

Datta³

et al. 2006

Cell Cycle

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“…GSK3b has been shown to be related to apoptosis in several studies [6,10,21]. Thapsigargin induced apoptosis of neuronal cells through activation of GSK3b, and this was prevented by LiCl [9].…”

Section: Discussionmentioning

confidence: 99%

“…A percentage of the total cell number was represented. The values are expressed as mean ± SD intracellular signaling factor in the canonical Wnt/b-catenin pathway in osteoblasts [2,5], and has previously been found to induce apoptosis [9,10,21]. Furthermore the activation and regulation of GSK3b are dependent on phosphorylation [22].…”

Section: Dex Induces Gsk3b Activation In Osteoblastsmentioning

confidence: 99%

“…Phosphorylation at Tyr-216 of GSK3b is shown to be required for GSK3b activity and function [8]. Indeed, inhibition of GSK3b leads to protection of many apoptotic conditions [9][10][11]. Nuclear GSK3b participates in regulation of many transcription factors, which influence many signaling pathway, and result in control of expression level of many genes [7].…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

et al. 2008

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Glucocorticoids (GCs), which play an important role in the normal regulation of bone remodeling, are widely used as anti-inflammatory and chemotherapeutic agents. However, continued exposure to GCs results in osteoporosis, which is partially due to apoptosis of osteoblasts and osteocytes. To understand the mechanism of how GCs induce cell death in osteoblasts, we examined apoptotic effects of dexamethasone (Dex), GC, on MC3T3-E1 osteoblast cells. Results revealed that Dex-induced apoptosis was inhibited by a GC receptor antagonist, mifepristone, and a general caspase inhibitor, Z-VAD-fmk, indicating that Dex induces apoptosis of MC3T3-E1 cells through the pathways involved in GC receptor and caspase. Glycogen synthase kinase 3b (GSK3b) is known to participate in apoptosis signaling in MC3T3-E1 cells. Dex activated both GSK3b and p38-mitogen-activated protein kinase (MAPK). The inhibition of GSK3b by inhibitor (LiCl) or small interference RNA (siRNA) decreased apoptosis. In contrast, the inhibition of p38-MAPK by inhibitor (SB203580) or siRNA did not decrease, but increase apoptosis. These results suggest that Dex-mediated apoptosis of osteoblasts is facilitated by GSK3b, but prevented by p38-MAPK.

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“…34,35 In hematopoietic cells inhibition of GSK3 kinase that is a kinase negatively regulated by Akt, leads to enhancement of Chk-1 (Ser 345) phosphorylation. 36 Etoposide treatment of these hematopoietic cells induces G2/M arrest in an Akt-and Chk-1-dependent manner indicating that in these cells increased Akt activity and the correlating increase in phosphorylation of Chk-1 stimulate G2 arrest. In A549, Calu1 and H596 NSCLC cell lines the staurosporine analog and Chk-1 inhibitor UCN-01 potentiate cisplatininduced apoptosis, which is correlated with abrogation of the S and G2 checkpoints.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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Hematopoietic cytokines enhance Chk1-dependent G2/M checkpoint activation by etoposide through the Akt/GSK3 pathway to inhibit apoptosis

Cited by 44 publications

References 36 publications

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

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