• BMB Reports
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• v.53 no.5
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• pp.272-277
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• 2020

Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)-p53-p21^Cip1/WAF1 pathway. The transcription factor "nuclear factor erythroid 2-related factor 2" (Nrf2) plays an important role in maintaining intracellular redox homeostasis. In this study, Nrf2 overexpression attenuated CK2 downregulation-induced ROS production and senescence markers including SA-β-gal staining and activation of p53-p21^Cip1/WAF1 in human breast (MCF-7) and colon (HCT116) cancer cells. CK2 downregulation reduced the transcription of Nrf2 target genes, such as glutathione S-transferase, glutathione peroxidase 2, and glutathione reductase 1. Furthermore, CK2 downregulation destabilized Nrf2 protein via inhibiting autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Finally, CK2 downregulation decreased the nuclear import of Nrf2 by deactivating AMP-activated protein kinase (AMPK). Collectively, our data suggest that both Keap1 stabilization and AMPK inactivation are associated with decreased activity of Nrf2 in CK2 downregulation-induced cellular senescence.

• Journal of Environmental Science International
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• v.16 no.2
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• pp.219-225
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• 2007

Endocrine disrupting compounds (EDC's) are chemicals that either mimic endogenous hormones interfering with pharmacokinetics or act by other mechanisms. Some endocrine disrupters were reported to be chemical substances that cause apoptosis in cells. A number of reports have indicated that 1,3-DCP, one of the EDC's may act as an endocrine disrupter and also has possible carcinogenic effects. 1,3-DCP, present in commercial protein hydrolysates used for human nutrition, are genotoxic and 1,3-dichloro-2-propanol induced tumors in rats. In the present study, it was investigated whether 1,3-DCP induces ROS generation and apotosis in A549 adenocarcinoma cells. Here we show that 1,3-DCP inhibits the growth of lung cancer cell lines and generates reactive oxygen species (ROS), a major cause of DNA damage and genetic instability, It was investigated that 1,3-DCP increases G1 phase cells after 12 hours, thereafter abruptly draws A549 cells to G0 state after 24 hours by flow cytometric analysis. 1,3-DCP induces p53 and $p21^{Cip1/WAF1}$ activation time- and dose-dependently by 24 hours, while the level $p21^{Cip1/WAF1}$ was decreased after 48 hours. These results suggest that 1,3-DCP, an EDC's generates ROS and regulates genes involved with cell cycle and apoptosis.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2655-2660
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• 2016

Background: Prostate cancer is the second most common male cancer and remains a leading cause of cancer death worldwide. Heterogeneity regarding recurrence, tumor progression and therapeutic response reflects the inadequacy of traditional prognostic factors and underlies interest in new genetic and molecular markers. In this work, we studied the prognostic value of the expression of 9 proteins, Ki-67, p53, Bcl-2, PSA, HER2, E-cadherin, $p21^{WAF1/Cip1}$, $p27^{Kip1}$ and $p16^{ink4a}$ in prostate cancer. Materials and Methods: We conducted a retrospective study of 50 prostate cancers diagnosed in Pathology Department of Farhet Hached Hospital, Sousse, Tunisia, during a period of 12 months. Clinico-pathological data and survival were investigated. Protein expression was analyzed by immunohistochemistry on archived material. Results: Expression or over-expression of Ki-67, p53, Bcl-2, PSA, HER2, E-Cadherin, $p21^{WAF1/Cip1}$, $p27^{Kip1}$ and $p16^{ink4a}$ was observed in 68%, 24%, 32%, 78%, 12%, 90%, 20%, 44% and 56% of cases, respectively. Overall five-year survival was 68%. A statistically significant correlation was observed between death occurrence and advanced age (p=0.018), degree of tumor differentiation (p=0.0001), perineural invasion (p=0.016) and metastasis occurrence (p=0.05). Death occurrence was significantly correlated with the expression of p53 (p=0.007), Bcl-2 (p=0.02), Ki-67 (p=0.05) and $p27^{Kip1}$ (p=0.04). Conclusions: The p53, Bcl-2, Ki-67 and $p27^{Kip1}$ proteins may be useful additional prognostic markers for prostate cancer. The use of these proteins in clinical practice can improve prognosis prediction, disease screening and treatment response of prostatic cancer.

• Proceedings of the Korean Society of Life Science Conference
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• 2003.05a
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• pp.143-143
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• 2003

• Radiation Oncology Journal
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• v.15 no.3
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• pp.187-195
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• 1997

Purpose : To analyze the involvement of apoptosis regulatory genes p53, $p21^{wart/cip1}$ bax and bcl-2 in induction of apoptosis by radiation in murine tumors. Materials and methods : The radiation-sensitive ovarian carcinoma OCa-1, and the radiation-resistant hepatocarcinorna HCa-I were used. Tumors, 8 mm in diameter, were irradiated with 25 Gy and at various times after irradiation, ranging from 1 to 48 h, were analyzed histologically for apoptosis and by western blot for alterations in the expression of these genes. The p53 status of the tumors were determined by the polymerase chain reaction-single strand conformation polymorphism assay. Results : Both tumors were positive for wild-type p53. Radiation inducesd apoptosis in OCa-1 but not in HCa-1. Apoptosis developed rapidly, peaked at 2 h after irradiation and returned to almost the background level at 48 h In OCa-1 radiation upregulated the expression of p53, $p21^{wart/cip1}$. and the bcl-2/bax ratio was decreased. In HCa-1 radiation increased the expression of both p53 and $p21^{wart/cip1}$, although the increase of the latter was small The bcl-2/bax ratio was greatly increased. In general the observed changes occurred within a few hours after irradiation, and either preceded or coincided with development of apoptosis Conclusions : The development of apoptosis required upregulation of both p53 and $p21^{wart/cip1}$ as well as a decrease in bcl-2/bax ratio. In contrast, an increase in bcl-2/bax ratio Prevented apoptosis in the presence of upregulated p53 and $p21^{wart/cip1}$ . These findings indentified the involvement of multiple oncogenes in apoptosis regulation in vivo and demonstrate the complexity that may be associated with the use of a single oncogene assessment for Predicting the outcome of cancer therapy with cytotoxic agents.

• Journal of Life Science
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• v.20 no.2
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• pp.281-291
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• 2010

We investigated the antioxidant effects of hederagenin 3-O-b-D-glucopyranosyl($1{\rightarrow}3$)-a-L-rhamnopyranosyl($1{\rightarrow}2$)-a-L-arabinopyranoside (HDL) isolated from root bark of Ulmus davidiana on the activity of enzymes related to reactive oxygen species (ROS) in human osteosarcoma U2OS cells. Cobalt chloride ($CoCl_2$), a transition metal, was used as an inducer of oxidative stress, generating hydrogen peroxide ($H_2O_2$) via increasing xanthine oxidase (XO) activity. The increased levels of $H_2O_2$, XO, ferritin, and ferritin iron by $CoCl_2$ were diminished effectively by co-treatment with HDL in U2OS cells. Furthermore, decreased levels of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) by $CoCl_2$ were highly increased by co-treatment with HDL in U2OS cells; however, the levels of glutathione peroxidase (GPx) did not change. The increased contents of TBARS related to lipid peroxidation were significantly reduced by HDL in U2OS cells. The concentration of GSH changed in a pattern that went against regulated TBARS by $CoCl_2$ and HDL. We examined the expression of p53, $p21^{CIP1/WAF1}$, and $p27^{KIP1}$ proteins related to oxidative stress and cell cycle regulation. As a result, the expression of $p27^{KIP1}$ modulated by $CoCl_2$ was not changed by HDL. However, the expression of p53 and $p21^{CIP1/WAF}$ increased by $CoCl_2$ was reduced by HDL in U2OS cells. Together with alteration of p53 and $p21^{CIP1/WAF1}$ proteins, the accumulated cells at G1 phase by $CoCl_2$ was decreased by HDL in U2OS cells. Our data suggests that HDL inhibits $CoCl_2$-generated ROS in U2OS cells, providing potentially new antioxidant compounds that are isolated from natural products.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2001.10b
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• pp.150-150
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• 2001

• Proceedings of the PSK Conference
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• 2001.04a
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• pp.184.1-184.1
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• 2001

• Proceedings of the PSK Conference
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• 2002.04a
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• pp.164.1-164.1
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• 2002

• Journal of Microbiology and Biotechnology
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• v.27 no.6
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• pp.1163-1170
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• 2017

Clostridium difficile releases two exotoxins, toxin A and toxin B, which disrupt the epithelial cell barrier in the gut to increase mucosal permeability and trigger inflammation with severe diarrhea. Many studies have suggested that enteric nerves are also directly involved in the progression of this toxin-mediated inflammation and diarrhea. C. difficile toxin A is known to enhance neurotransmitter secretion, increase gut motility, and suppress sympathetic neurotransmission in the guinea pig colitis model. Although previous studies have examined the pathophysiological role of enteric nerves in gut inflammation, the direct effect of toxins on neuronal cells and the molecular mechanisms underlying toxin-induced neuronal stress remained to be unveiled. Here, we examined the toxicity of C. difficile toxin A against neuronal cells (SH-SY5Y). We found that toxin A treatment time- and dose-dependently decreased cell viability and triggered apoptosis accompanied by caspase-3 activation in this cell line. These effects were found to depend on the up-regulation of reactive oxygen species (ROS) and the subsequent activation of p38 MAPK and induction of $p21^{Cip1/Waf1}$. Moreover, the N-acetyl-$\text\tiny L$-cysteine (NAC)-induced down-regulation of ROS could recover the viability loss and apoptosis of toxin A-treated neuronal cells. These results collectively suggest that C. difficile toxin A is toxic for neuronal cells, and that this is associated with rapid ROS generation and subsequent p38 MAPK activation and $p21^{Cip1/Waf1}$ up-regulation. Moreover, our data suggest that NAC could inhibit the toxicity of C. difficile toxin A toward enteric neurons.