• Title, Summary, Keyword: Bax. p21

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Inhibitory Effect of Resveratrol on Lipopolysaccharide-induced p21 (WAF1/CIP1) and Bax Expression in Astroglioma C6 Cells (C6 신경교세포에서 lipopolysaccharide에 의한 p21 (WAF1/CIP1) 및 Bax의 발현증가에 미치는 resveratrol의 영향)

  • Kim, Young-Ae;Lim, Sun-Young;Rhee, Sook-Hee;Choi, Yung-Hyun
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.19 no.1
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    • pp.124-129
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    • 2005
  • Resveratrol, a phytoalexin found at high levels in grapes and in grape products such as red wine, has been reported to possess a wide range of biological and pharmacological activities including anti-oxident, anti-inflammatory, anti-mutagenic, and anti-carcinogenic effects, but its molecular mechanism is poorly understood. In this study, we examined the effects of resveratrol on lipopolysaccharide (LPS)-induced growth inhibitory activity and cell growth-regulatory gene products in astroglioma C6 cells to elucidate its possible mechanism for anti-cytotoxicity. It is shown that LPS induced time-dependent growth inhibition and morphological changes of C6 cells, which were recovered by pre-treatment with resveratrol. The anti-proliferative effect of LPS was associated with the induction of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) expression assessed by RT-PCR and Western blot analysis in time-dependent manner in C6 cells. In addition, the pro-apoptotic Bax expression was also up-regulated in LPS-treated C6 cells without alteration of anti-apoptotic Bcl-2 and Bcl-XL expression. However, resveratrol significantly inhibited LPS-induced p53, p21 and Bax levels, suggesting that the modulation of p53, p21 and Bax levels could be one of the possible pathways by which resveratrol functions as anti-cytotoxic agent.

Induction of Apoptosis and Expression of Apoptosis-related Gene Products in Response to Radiation in Murine Tumors (방사선에 대한 종양의 반응에서 아포프토시스의 유도와 이에 관련되는 유전자 발현)

  • Seong, Jin-Sil;Hunter, Nancv;Milas, Luka
    • 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.

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Anti-proliferative Effects of Bee Venom through Induction of Bax and Cdk Inhibitor p21WAF1/CIP1 in Human Lung Carcinoma Cells (Bax 및 Cdk inhibitor p21WAF1/CIP1 발현 증가에 의한 bee venom의 A549 인체폐암세포 성장억제)

  • Choi, Yung-Hyun
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.19 no.1
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    • pp.167-173
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    • 2005
  • To investigate the possible molecular mechanism (s) of bee venom as a candidate of anti-cancer drug, we examined the effects of the compound on the growth of human lung carcinoma cell line A549. Bee venom treatment declined the cell growth and viability of A549 cells in a concentration-dependent manner, which was associated with induction of apoptotic cell death. Bee venom down-regulated the levels of anti-apoptotic genes such as Bcl-2 and Bcl-XS/L, however, the levels of Bax, a pro-apoptotic gene, were up-regulated. Bee venom treatment induced not only tumor suppressor p53 but also cyclin-dependent kinase inhibitor p21WAF1/CIP1 expression in a dose-dependent manner. Furthermore, bee venom treatment induced the down-regulation of telomerase reverse transcriptase mRNA and telomeric repeat binding factor expression of A549 cells, however, the levels of telomerase-associated protein-1 and c-myc were not affected. Taken together, these findings suggest that bee venom-induced inhibition of human lung cancer cell growth is associated with the induction of apoptotic cell death via regulation of several major growth regulatory gene products, and bee venom may have therapeutic potential in human lung cancer.

Tumor-suppressor Protein p53 Sensitizes Human Colorectal Carcinoma HCT116 Cells to 17α-estradiol-induced Apoptosis via Augmentation of Bak/Bax Activation (17α-Estradiol에 의한 인체 대장암 세포주 HCT116의 에폽토시스에 수반되는 Bak/Bax의 활성화에 미치는 종양억제단백질 p53의 강화효과)

  • Han, Cho Rong;Lee, Ji Young;Kim, Dongki;Kim, Hyo Young;Kim, Se Jin;Jang, Seokjoon;Kim, Yoon Hee;Jun, Do Youn;Kim, Young Ho
    • Journal of Life Science
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    • v.23 no.10
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    • pp.1230-1238
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    • 2013
  • The regulatory effect of the tumor-suppressor protein p53 on the apoptogenic activity of $17{\alpha}$-estradiol ($17{\alpha}-E_2$) was compared between HCT116 ($p53^{+/+}$) and HCT116 ($p53^{-/-}$) cells. When the HCT116 ($p53^{+/+}$) and HCT116 ($p53^{-/-}$) cells were treated with $2.5{\sim}10{\mu}M$ $17{\alpha}-E_2$ for 48 h or with $10{\mu}M$for various time periods, cytotoxicity and an apoptotic sub-$G_1$ peak were induced in the HCT116 ($p53^{+/+}$) cells in a dose- and time-dependent manner. However, the HCT116 ($p53^{-/-}$) cells were much less sensitive to the apoptotic effect of $17{\alpha}-E_2$. Although $17{\alpha}-E_2$ induced aberrant mitotic spindle organization and incomplete chromosome congregation at the equatorial plate, $G_2/M$ arrest was induced to a similar extent in both cell types. In addition, $17{\alpha}-E_2$-induced activation of Bak and Bax, ${\Delta}{\Psi}m$ loss, and PARP degradation were more dominant in the HCT116 ($p53^{+/+}$) than in the HCT116 ($p53^{-/-}$) cells. In accordance with enhancement of p53 phosphorylation (Ser-15) and p53 levels, p21 and Bax levels were elevated in the HCT116 ($p53^{+/+}$) cells treated with $17{\alpha}-E_2$. The HCT116 ($p53^{-/-}$) cells exhibited barely or undetectable levels of p21 and Bax, regardless of $17{\alpha}-E_2$ treatment. On the other hand, although the level of Bcl-2 was slightly lower in the HCT116 ($p53^{+/+}$) than in the HCT116 ($p53^{-/-}$) cells, it remained relatively constant after the $17{\alpha}-E_2$ treatment. Together, these results show that among the components of the $17{\alpha}-E_2$-induced apoptotic-signaling pathway, which proceeds through mitotic spindle defects causing mitotic arrest, subsequent activation of Bak and Bax and the mitochondria-dependent caspase cascade, leading to PARP degradation, $17{\alpha}-E_2$-induced activation of Bak and Bax is the upstream target of proapoptotic action of p53.

Effect of Resveratrol on the Induction of Cdk Inhibitor p21 and Pro-apoptotic Bax Expression by amyloid-β in Astroglioma C6 Cells (신경교 세포에서 resveratrol이 amyloid-β에 의해 유도되는 Cdk inhibitor p21 및 Bax 발현의 감소 효과)

  • Kim Young Ae;Lim Sun-Young;Ko Woo Shin;Choi Byung Tae;Lee Yong Tae;Rhee Sook-Hee;Park Kun-Young;Lee Won-Ho;Choi Yung Hyun
    • Journal of Life Science
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    • v.15 no.2
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    • pp.169-175
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    • 2005
  • Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. $Amyloid-\beta$ deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease. In this study, we have explored the effects of resveratrol on $amyloid-\beta-peptide-mediated$ cytotoxicity in vitro and modulation of cell growth-regulatory gene products in astroglioma C6 cells to elucidate its possible mechanism for anti-cytotoxicity. Exposure of C6 cells to $Amyloid-\beta$ resulted in dose-dependent growth inhibition and morphological changes of C6 cells, which were recovered by pre-treatment with resveratrol. The anti-proliferative effect of $amyloid-\beta$ was associated with the induction of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) expression assessed by RT-PCR and Western blot analysis in time-dependent manner in C6 cells. In addition, the pro-apoptotic Bax expression was also up-regulated in $amyloid-\beta-treated$ C6 cells without alteration of anti-apoptotic Bcl-2 and $Bcl-X_L$ expression. However, pre-treatment of resveratrol significantly inhibited $amyloid-\beta-induced$ p53, p21 and Bax levels, suggesting that the modulation of p53, p21 and Bax levels could be one of the possible pathways by which resveratrol functions as anti-cytotoxic agent. Our results demonstrate that resveratrol may enhance the protection against $amyloid-\beta-induced$ cytotoxicity by promoting the survival of glial cells.

Expressions of Apoptotic Genes (survivin, bcl-2, bax) and Clinical Relevance in Osteosarcoma (골육종에서 세포 사멸 관련 유전자 survivin, bcl-2, bax의 발현과 임상적 의의)

  • Kang, Hyun-Guy;Kim, Han-Soo;Lee, Mi-Ra;Seol, So-Mi;Oh, Joo-Han;Lee, Sang-Hoon;Kang, Gyeong-Hoon
    • The Journal of the Korean bone and joint tumor society
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    • v.11 no.2
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    • pp.118-125
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    • 2005
  • Purpose: The expression of apoptosis-related genes, such as survivin, bcl-2, and bax has been examined in the human osteosarcoma and then evaluated the correlation with clinical data of patients. Materials and Methods: Fifty human osteosarcoma specimens were established from incisional biopsy and examination of survivin, bcl-2, and bax by immunohistochemical study was performed. We investigated the correlation of survivin, bcl-2, bax and their two or three combined expressions with clinical data including the response of chemotherapy, local recurrence, distance metastasis, and oncologic outcome. Results: Survivin was showed in 26 cases (52%), bcl-2 in 23 cases (46%), and bax in 21 cases (42%) osteosarcoma. And coexpression of survivin and bcl-2 was showed in 19 cases (38%), survivin and bax in 13 cases (26%), bcl-2 and bax in 8 cases (16%), and all three expression was showed in 8 cases (16%). There was no correlation between their apoptosis related gene and histologic difference, the presence of local recurrence and distant metastasis. Whereas neoadjuvant chemotherapy response correlated with bcl-2 expression (P=0.04), and survivin and bcl-2 coexpression (P=0.044) with poor chemoresponse. The rate of died of disease was correlated with bcl-2 (P=0.001), survivin and bcl-2 coexpression (P=0.027) with bad outcome. Survival curves of bcl-2 (P=0.0075), survivin and bcl-2 (P=0.0012) was showed negative correlation in the Kaplan-Meier method. Conclusion: The apoptosis related gene expression was relatively high in osteosarcoma, bcl-2 expression was correlated with poor chemotherapy response and poor survival rate, but survivin was correlated with this oncologic outcome only in the bcl-2 coexpression. The examination of immunohistochemical stain of apoptosis related gene in osteosarcoma could be helpful in the judgment of osteosarcoma prognosis.

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Tumor Suppressor Protein p53 Promotes 2-Methoxyestradiol-Induced Activation of Bak and Bax, Leading to Mitochondria-Dependent Apoptosis in Human Colon Cancer HCT116 Cells

  • Lee, Ji Young;Jee, Su Bean;Park, Won Young;Choi, Yu Jin;Kim, Bokyung;Kim, Yoon Hee;Jun, Do Youn;Kim, Young Ho
    • Journal of Microbiology and Biotechnology
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    • v.24 no.12
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    • pp.1654-1663
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    • 2014
  • To examine the effect of tumor suppressor protein p53 on the antitumor activity of 2-methoxyestradiol (2-MeO-$E_2$), 2-MeO-$E_2$-induced cell cycle changes and apoptotic events were compared between the human colon carcinoma cell lines HCT116 ($p53^{+/+}$) and HCT116 ($p53^{-/-}$). When both cell types were exposed to 2-MeO-$E_2$, a reduction in the cell viability and an enhancement in the proportions of $G_2/M$ cells and apoptotic sub-$G_1$ cells commonly occurred dose-dependently. These 2-MeO-$E_2$-induced cellular changes, except for $G_2/M$ arrest, appeared to be more apparent in the presence of p53. Immunofluorescence microscopic analysis using anti-${\alpha}$-tubulin and anti-lamin B2 antibodies revealed that after 2-MeO-$E_2$ treatment, impaired mitotic spindle network and prometaphase arrest occurred similarly in both cell types. Following 2-MeO-$E_2$ treatment, only HCT116 ($p53^{+/+}$) cells exhibited an enhancement in the levels of p53, p-p53 (Ser-15), $p21^{WAF1/CIP1}$, and Bax; however, the Bak level remained relatively constant in both cell types, and the Bcl-2 level decreased only in HCT116 ($p53^{+/+}$) cells. Additionally, mitochondrial apoptotic events, including the activation of Bak and Bax, loss of ${\Delta}{\psi}m$, activation of caspase-9 and -3, and cleavage of lamin A/C, were more dominantly induced in the presence of p53. The Bak-specific and Bax-specific siRNA approaches confirmed the necessity of both Bak and Bax activations for the 2-MeO-$E_2$-induced apoptosis in HCT116 cells. These results show that among 2-MeO-$E_2$-induced apoptotic events, including prometaphase arrest, up-regulation of Bax level, down-regulation of Bcl-2 level, activation of both Bak and Bax, and mitochondria-dependent caspase activation, the modulation of Bax and Bcl-2 levels is the target of the pro-apoptotic action of p53.

Apoptotic Cell Death by Methanol Extract of Phellinus linteus-Barley Corn in Human Leukemic U937 Cells through Induction of p21 and Bax, and Activation of Caspase-3 (상황보리 추출물에 의한 p21 및 Bax 발현 증가와 caspase 활성화를 통한 U937 인체백혈병 세포의 apoptosis 유발)

  • Park, Cheol;Kim, Hyun-Joog;Chung, Kyung-Tae;Yoon, Tae-Kyung;Choi, Byung-Tae;Lee, Yong-Tae;Park, Dong-Il;Choi, Yung-Hyun
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.21 no.5
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    • pp.1226-1232
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    • 2007
  • Phellinus linteus is a well-known Oriental medicinal fungus that has various biological activities, including immunomodulatory and anti-tumor activities, the mechanisms of which are poorly understood. In the present study, we investigated the anti-proliferative activity of the methanol extract of P. linteus-Barley corn (MEPLB) in human lekemic U937 cells. It was found that exposure of U937 cells to MEPLB resulted morphological change and growth inhibition in a dose-dependent manner as measured by trypan blue count and MTT assay. Upon treatment with MEPLB, U937 cells developed many of the hallmark features of apoptosis, including condensation of chromatin and an increase in the sub-G1 population suggesting that the anti-proliferative effect of MEPLB is associated with the induction of apoptosis. The anti-proliferative and apoptotic effects of MEPLB were connected with a marked induction of the pro-apoptotic Bax and cyclin-dependent kinase (Cdk) inhibitor p21 in a p53-independent manner. Additionally, MEPLB treatment significantly induced the caspase-3 activity in U937 cells. Taken together, the present results suggest that apoptotic signals evoked by MEPLB in human leukemic U937 cells may converge caspase-3 activation through an up-regulation of Bax rather than a down-regulation of Bcl-2 or Bel-xL.

Antiproliferative Effect of Mistletoe Extract Added Kimchi in Human Lung Carcinoma A549 Cells (겨우살이 물추출물 첨가 김치의 A549 인체 폐암 세포 증식저해 효과)

  • Kil, Jung-Ha
    • Journal of Life Science
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    • v.27 no.12
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    • pp.1507-1514
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    • 2017
  • The purpose of this study aimed at examining the antiproliferative effect of kimchi (kimchi B) adding mistletoe extract known as an anticancer function to improve the functions of kimchi. The study investigated the antiproliferative effect through hemocytometer counts and MTT assay, apoptosis induction through DAPI staining, and mRNA expression through RT-PCR using human lung carcinoma A549 cells. The standardized kimchi (Kimchi A) was used as a control group. As a result of hemocytometer counts and the MTT assay, it was found that kimchi samples inhibited the growth of A549 cells in a concentration-dependent manner. Kimchi B induced apoptosis in A549 cells through DAPI staining. The apoptosis induced by kimchi B was associated with the increase in the expression of pro-apoptotic Bax and with the decrease in the expression of anti-apoptotic Bcl-2 and Bcl-xL. Also, kimchi B influenced the increase in the expression of p21 mRNA, but did not have the effect on the expression of p53 mRNA. In conclusion, the antiproliferative effect of kimchi B was due to apoptosis induced by increasing Bax and decreasing Bcl-2, and increasing p21. The findings will be utilized to develop kimchi with the improved function for the patients having cancer.

Protection of Codonopis pilosula Extract against Cell Death of SK-N-MC Neuroblastoma Cells Treated with $H_2O_2$ (만삼(蔓蔘)의 과산화수소에 의한 SK-N-MC의 세포사에 미치는 영향)

  • Lee, Seon-Goo
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.22 no.2
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    • pp.328-332
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    • 2008
  • The purpose of this study was to identify the protective effect of Codonopis pilosula extract on cell death induced by $H_2O_2$ in SK-N-MC neuroblastoma cells. We measured the antioxidant effect by DPPH radical scavenging analysis, BSA analyssis and examined the cell viability by crystal violet and cytochrome C, Bax, Bcl-2, p53, p21 by using Western blot analysis. Codonopis pilosula extract scavenged DPPH radical in a dose-dependent manner and shown direct free radical scavenging effect, suggested that Codonopis pilosula extract have antioxidant effect in vitro. Treatment of cells with hydrogen peroxide, a reactive oxygen species, was to induce cell death and pretreatment with Codonopis pilosula extract attenuated the occurrence of $H_2O_2-induced$ cell death. To elucidate the protective mechanisms of action of Codonopis pilosula extract, Western blot analyses for Bcl-2 and Bax expression and cytochrome c release were carried out. Pretreatment with Codonopis pilosula extract induced the expression of Bcl-2 and suppressed the release of cytochrome c and Bax into the cytosol, thereby arresting $H_2O_2-induced$ apoptotic cell death. Especially p21 and p53 were decreased prior to $H_2O_2$ treatment. These results suggest that Codonopis pilosula extract is associated with the cell cycle and anti-apoptotic cell death.