Activation of c-jun N-terminal kinase/stress-activated protein kinase and the decreased ratio of Bcl-2 to Bax are associated with the auto-oxidized dopamine-induced apoptosis in PC12 cells

Kang, Chi‐Dug; Jang, Jung‐Hee; Kim, Kwang-Woon; Lee, Heon-Jin; Jeong, Choon Sik; Kim, Cheol-Min; Kim, Sun‐Hee; Chung, Byung-Seon

doi:10.1016/s0304-3940(98)00751-4

Cited by 61 publications

(44 citation statements)

References 17 publications

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“…In an effort to acquire more insight into the antimitogenic effect of 2ME observed in cell proliferation studies previously conducted in our laboratory (36), haematoxylin and eosin cell staining was used to determine the morphological characteristics of cytoplasm and nuclear components of WHCO3 cells after exposure to 10 −6 M 2ME. The latter indicates reduced quantity of DNA or hypercondensed DNA that may represent apoptotic bodies, as others and we have previously illustrated (15)(16)(17). However, 2ME had no influence on the anaplastic thyroid KAT-4 cancer cells (29), supporting the idea that the action mechanism of 2ME is not clearly defined and appears to vary depending on cell type (23).…”

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confidence: 74%

Influence of 2-methoxyestradiol on cell morphology and Cdc2 Kinase activity in WHCO3 esophageal carcinoma cells

Joubert

Marais

2007

Biomed. Res.

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The influence of 1 × 10 −6 M exogenous 2-methoxyestradiol (2ME) was investigated on nuclear and cytoplasmic morphology, as well as Cdc (cell division cycle) 2 kinase activity in WHCO3 esophageal carcinoma cells. Mitotic indices after 18 h of 2ME exposure revealed an increase in metaphase cells (9.0%) when compared to the vehicle-treated cells (0.9%). 2ME-treated cells showed apoptotic cells at 5.6% after 18 h of exposure to dimethyl sulphoxide, compared to 0.9% in vehicle-treated cells. Increased morphological characteristics of apoptosis were observed in 2ME-treated cells after 21.5 h of exposure. Twelve percent of cells were in apoptosis when compared to the 1.6% of vehicle-treated cells. Furthermore, 42.4% of cells were arrested in metaphase after 21.5 h of 2ME exposure compared to 2.9% of vehicle-control cells present in metaphase. Cdc2 kinase activity was statistically significantly increased (1.7-fold) (P < 0.005) after 18 h of 2ME exposure when compared to vehicle-treated controls. Although the mechanism of 2ME's action on esophageal carcinoma cells is not yet elucidated, the present study revealed that 2ME caused metaphase arrest, as well as an increase in Cdc2 kinase activity that culminated in the induction of apoptosis in these cells.2-Methoxyestradiol (2ME) is a naturally occurring physiological estrogen metabolite of 17beta-estradiol and considered as an antimitogenic compound and tubulin poison. Early research on 2ME's biological activity stated its effect on mitotic spindles and cell cycle progression (32). It has been shown to inhibit cell proliferation and to induce apoptosis in a large variety of tumor cells and is harmless to most normal cells (21). 2ME exerts both antiangiogenic and antitumor effects regardless of the cell's hormone receptor status (10,19,23,24,32,34). 2ME causes mitotic accumulation and abnormal mitotic spindle formation in both estrogen receptor (ER)-positive and negative cells (23,24,32).Recently, researchers have demonstrated the antiangiogenic influence of oral 2ME on a laser-induced murine model of choroidal neovascularization with no side effects of toxicity or weight loss being observed (9). investigated the efficacy on growth inhibition of 2ME on human hepatocellular carcinoma in vitro (31). 2ME caused a reduction in cell growth in these cells and it was concluded that the mechanism of action appears to be induction of apoptosis. SK-Hep1 hepatocellular carcinoma cells were the most sensitive to 2ME and an up-regulation of the p53 and p21 proteins was observed. However, normal human hepatocytes were not influenced when treated with 2ME (31). Roswall et al. (2006) demonstrated 2ME's antiproliferative effects in five human anaplastic thyroid carcinoma cell lines (HTh7, HTh 74, HTh83, C643, and SW1736) after treatment with 2ME. It was revealed that a G 2 /M-arrest was followed by an increased fraction of cells present in sub-G 1 (29). The

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supporting

confidence: 74%

Influence of 2-methoxyestradiol on cell morphology and Cdc2 Kinase activity in WHCO3 esophageal carcinoma cells

Joubert

Marais

2007

Biomed. Res.

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“…There appears to be a reasonably linear relationship between the degree of oxidative stress, the formation of disul®de species and the induction of stress responsive proteins. Thioredoxin has been the best characterized cysteine-rich redoxresponsive protein implicated in the regulation of several stress responsive proteins via direct or intermediate interactions (reviewed in Schulze-Ostho et al, 1995; Sen and Packer, 1996; Flohe et al, 1997; Kuo et al, 1995Cavigelli et al, 1996Ludwig et al, 1998Kilk et al, 1996Lim et al, 1997Duhe et al, 1998Krejsa et al, 1997Kang et al, 1998Lui et al, 1998 Piette et al, 1997). The recent identi®cation of thioredoxin as an inhibitor of stress kinase ASK1 (Saitoh et al, 1998), has shed new light on the modes of redox regulatable stress response.…”

Section: Ros-induced Modi®cation Of Redox Sensitive Proteins Which Rementioning

confidence: 99%

Role of redox potential and reactive oxygen species in stress signaling

et al. 1999

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Stress-activated signaling cascades are a ected by altered redox potential. Key contributors to altered redox potential are reactive oxygen species (ROS) which are formed, in most cases, by exogenous genotoxic agents including irradiation, in¯ammatory cytokines and chemical carcinogens. ROS and altered redox potential can be considered as the primary intracellular changes which regulate protein kinases, thereby serving as an important cellular component linking external stimuli with signal transduction in stress response. The mechanisms, which underlie the ROS-mediated response, involve direct alteration of kinases and transcription factors, and indirect modulation of cysteine-rich redox-sensitive proteins exempli®ed by thioredoxin and glutathione Stransferase. This review summarizes the current understanding of the mechanisms contributing to ROS-related changes in key stress activated signaling cascades.

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“…Bcl-2 is perceived as anti-apoptotic, whereas Bax can be regarded as pro-apoptotic and an increased ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2 can be associated with apoptosis. The pro-and anti-apoptotic Bcl-2 family of proteins are responsible for either the induction or prevention of mitochondrial membrane permeability important in regulating cytochrome c release from mitochondria (2,6,13,16,28).…”

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confidence: 99%

Influence of prostaglandin A2 on Bax, Bcl-2 and PCNA expression in MCF-7 cells

et al. 2006

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The effects of 20 μg/mL exogenous prostaglandin A 2 (PGA 2 ) were determined on Bax, Bcl-2 and proliferating cell nuclear antigen (PCNA) expression levels in MCF-7 cells. Flow cytometric analysis indicated a pronounced increase in the S phase and a decrease in the G 1 phase, whereas a significant increase in the DNA content preceding the G 0 /G 1 peak was also observed after 48 h of exposure to PGA 2 . Confirmation of apoptosis was determined after 12 h, 36 h and 48 h of PGA 2 exposure employing the mitosensor reagent that detects potential changes in the mitochondrial membrane. Twenty-eight percent of PGA 2 -exposed cells were in apoptosis when compared to the 7.1% vehicle-treated cells after 48 h. PGA 2 exposure led to statistically significant increase (1.25-fold) over vehicle-treated controls in Bax expression levels. Decreases in Bcl-2 (0.79-fold), as well as PCNA (0.69-fold) expression levels over vehicle-treated controls were observed. The Bax/Bcl-2 ratio for PGA 2 -exposed cells was 2.7. The present study suggests that an accumulation in the S phase, a decrease in expression levels of PCNA, as well as an altered ratio in favor of Bax, could lead to the induction of apoptosis in these cells.Research has shown that prostaglandin A 2 (PGA 2 ), a cyclopentenone and endogenous metabolite derived from arachidonic acid, exhibits potent anti-proliferative activity in vivo (5,14,20,22) and in vitro (1, 17-19, 21, 23). Concentration-dependent studies from previous research (12) revealed that 20 μg/mL results in optimal growth inhibition in vitro. This was confirmed in our laboratory where IC 50 = 20 μg/ mL was determined (results not shown). PGA 2 inhibited proliferation of tumor cells depending on dose, duration of exposure and cell type (12). In addition, we have demonstrated that the breast adenocarcinoma cells, MCF-7, were more susceptible to the anti-mitogenic effects of PGA 2 when compared to human epithelial cervix carcinoma (HeLa) cells (11). Furthermore, degree of differentiation of oesophageal carcinoma cells was also shown to influence tumor cell susceptibility to the anti-mitogenic effects of PGA 2 . More differentiated and normal cells appeared to be less affected, while more pronounced effects were observed in less differentiated cell lines (12).Since PGA 2 targets active proliferating cells and plays an active role in the induction of apoptosis, especially in cells that present with carcinogenic properties (12,25), the aim of this study was to confirm the anti-mitogenic effects of PGA 2 and to investigate the influence of PGA 2 on Bax, Bcl-2 and PCNA expression in MCF-7 cells in order to suggest a possible mechanism for induction of apoptosis.

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Activation of c-jun N-terminal kinase/stress-activated protein kinase and the decreased ratio of Bcl-2 to Bax are associated with the auto-oxidized dopamine-induced apoptosis in PC12 cells

Cited by 61 publications

References 17 publications

Influence of 2-methoxyestradiol on cell morphology and Cdc2 Kinase activity in WHCO3 esophageal carcinoma cells

Influence of 2-methoxyestradiol on cell morphology and Cdc2 Kinase activity in WHCO3 esophageal carcinoma cells

Role of redox potential and reactive oxygen species in stress signaling

Influence of prostaglandin A2 on Bax, Bcl-2 and PCNA expression in MCF-7 cells

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