• Title/Summary/Keyword: extrinsic apoptosis

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Inhibitory Effects of Gardeniae Fructus on Apoptosis induced by 4-HNE in PC-12 Cell (치자(梔子)의 Apoptosis유발 억제효과)

  • Han, Yong-Soo;Lee, Tae Hee;Kim, Youn-Sub
    • Herbal Formula Science
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    • v.26 no.3
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    • pp.195-205
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    • 2018
  • Objectives : The purpose of this study was to observe the effects of Gardeniae Fructus on 4-HNE-induced apoptosis in PC-12 cell. Methods : A MTT assay was conducted to observe the cytotoxicity of Gardeniae Fructus on the PC-12 cell viability and the cytoprotective effects of Gardeniae Fructus on PC-12 cell against oxidative stress caused by 4-HNE. And western blot was conducted to observe the expression of Bax, Bcl-2, Caspase-3, $TNF-{\alpha}$ proteins which are involved in intrinsic and extrinsic apoptosis pathway. Results : 25, 50, 100, 200 and $400{\mu}g/m{\ell}$ of Gardeniae Fructus water extract had no cytotoxicity on PC-12 cell. $200{\mu}g/m{\ell}$ of Gardeniae Fructus water extract had significant cytoprotective effect on PC-12 cell against oxidative stress caused by 4-HNE. The expression of Bax protein in 50, 100 and $200{\mu}g/m{\ell}$ of Gardeniae Fructus was significantly decreased in PC-12 cell. The expression of Bcl-2 protein in $200{\mu}g/m{\ell}$ of Gardeniae Fructus was significantly increased in PC-12 cell. The expression of Caspase-3 protein in 100 and $200{\mu}g/m{\ell}$ of Gardeniae Fructus was significantly decreased in PC-12 cell. The expression of $TNF-{\alpha}$ protein in $50{\mu}g/m{\ell}$ of Gardeniae Fructus was significantly decreased in PC-12 cell. Conclusions : These results suggest that Gardeniae Fructus water extract is effective to protect PC-12 cell from 4-HNE induced apoptosis.

Oxysterol 25-hydroxycholesterol as a metabolic pathophysiological factors of osteoarthritis induces apoptosis in primary rat chondrocytes

  • Seo, Yo-Seob;Cho, In-A;Kim, Tae-Hyeon;You, Jae-Seek;Oh, Ji-Su;Lee, Gyeong-Je;Kim, Do Kyung;Kim, Jae-Sung
    • The Korean Journal of Physiology and Pharmacology
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    • v.24 no.3
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    • pp.249-257
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    • 2020
  • The aim of the present study was to investigate the pathophysiological etiology of osteoarthritis that is mediated by the apoptosis of chondrocytes exposed to 25-hydroxycholesterol (25-HC), an oxysterol synthesized by the expression of cholesterol-25-hydroxylase (CH25H) under inflammatory conditions. Interleukin-1β induced the apoptosis of chondrocytes in a dose- dependent manner. Furthermore, the production of 25-HC increased in the chondrocytes treated with interleukin-1β through the expression of CH25H. 25-HC decreased the viability of chondrocytes. Chondrocytes with condensed nucleus and apoptotic populations increased by 25-HC. Moreover, the activity and expression of caspase-3 were increased by the death ligand-mediated extrinsic and mitochondria-dependent intrinsic apoptotic pathways in the chondrocytes treated with 25-HC. Finally, 25-HC induced not only caspase-dependent apoptosis, but also induced proteoglycan loss in articular cartilage ex vivo cultured rat knee joints. These data indicate that 25-HC may act as a metabolic pathophysiological factor in osteoarthritis that is mediated by progressive chondrocyte death in the articular cartilage with inflammatory condition.

Inhibition of cell growth and induction of apoptosis by bilobalide in FaDu human pharyngeal squamous cell carcinoma

  • Jeong, Kyung In;Kim, Su-Gwan;Go, Dae-San;Kim, Do Kyungm
    • International Journal of Oral Biology
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    • v.45 no.1
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    • pp.8-14
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    • 2020
  • Bilobalide isolated from the leaves of Ginkgo biloba has several pharmacological activities such as neuroprotective, anti-inflammatory, and anticonvulsant. However, the effect of bilobalide on cancer has not been clearly established. The main purpose of this study was to investigate the effect of bilobalide on cell growth and apoptosis induction in FaDu human pharyngeal squamous cell carcinoma. This was examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, nuclear 4′,6-diamidino-2-phenylindole dihydrochloride staining, DNA fragmentation analysis, and immunoblotting. Bilobalide inhibited the growth of FaDu cells in dose- and time-dependent manners. Treatment with bilobalide resulted in nuclear condensation and DNA fragmentation in FaDu cells. Furthermore, it promoted the proteolytic cleavage of procaspase-3/-7/-8/-9 with increase in the amount of cleaved caspase-3/-7/-8/-9. Bilobalide-induced apoptosis in FaDu cells was mediated by the expression of Fas and the activation of caspase-8, caspase-3, and poly (ADP-ribose) polymerase. Immunoblotting revealed that the antiapoptotic mitochondrial protein Bcl-2 was downregulated, but the proapoptotic protein Bax was upregulated by bilobalide in FaDu cells. Bilobalide significantly increased Bax/Bcl-2 ratio. These results suggest that bilobalide inhibits cell proliferation and induces apoptosis in FaDu human pharyngeal squamous cell carcinoma via both the death receptor-mediated extrinsic apoptotic pathway and the mitochondrial-mediated intrinsic apoptotic pathway.

Prostate Apoptosis Response-4 (Par-4) as a Cancer Therapeutic Target (암 치료 표적으로써 prostate apoptosis response-4 (Par-4))

  • Woo, Seon Min;Kwon, Taeg Kyu
    • Journal of Life Science
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    • v.25 no.8
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    • pp.947-952
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    • 2015
  • Prostate apoptosis response-4 (Par-4) was originally identified in androgen-independent prostate cancer cells undergoing apoptosis. Par-4 is ubiquitously expressed in normal cells and tissues, but it is downregulated in several types of cancers. Par-4 is a 38 kDa tumor suppressor protein encoded by the PARW gene. Par-4 promotes apoptosis in a variety of cancerous cells, but not in normal cells. In this review, we focused on the structure, expression and function of Par-4 in apoptotic signaling pathway. Functional domains of Par-4 include two nuclear localization sequences (NLS), a leucine zipper (LZ) domain, a nuclear export sequence (NES) and selective for apoptosis in cancer cell (SAC) domain. Many studies have underlined the importance of Par-4 in preventing cancer development. The activity of Par-4 is differently regulated by localization of intracellular and extracellular Par-4. Intracellular Par-4 inhibits Akt- and NF-κB-mediated cell survival pathways and downregulates Bcl-2 expression. Extracellular Par-4 activates the extrinsic apoptotic pathway by binding to cell surface receptor GRP78, a stress response protein that is in the endoplasmic reticulum (ER). Endogenous Par-4 sensitizes cancer cells to various apoptotic stimuli, while exogenous Par-4 enhances SAC domain-dependent apoptosis in cancer cells, but not normal cells. Therefore, Par-4 is an attractive target for cancer therapy.

Induction of Apoptosis by Hwangheuk-san in AGS Human Gastric Carcinoma Cells through the Generation of Reactive Oxygen Species and Activation of Caspases (AGS 인체 위암세포에서 황흑산에 의한 ROS 생성 및 caspase 활성 의존적 apoptosis 유발)

  • Hong, Su Hyun;Park, Cheol;Kim, Kyoung Min;Choi, Yung Hyun
    • Journal of Life Science
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    • v.25 no.11
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    • pp.1235-1243
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    • 2015
  • Hwangheuk-san (HHS) is a Korean multi-herb formula comprising four medicinal herbs. HHS, which was recorded in “Dongeuibogam,” has been used to treat patients with inflammation syndromes and digestive tract cancer for hundreds of years. However, little is known about its anti-tumor efficacy. The present study investigated the pro-apoptotic effect and mode of action of HHS against AGS human gastric carcinoma cells. HHS inhibited the cell growth of AGS cells in a dose-dependent manner, which was associated with the induction of apoptotic cell death, as evidenced by the formation of apoptotic bodies, chromatin condensation, and an accumulation of cells in the sub-G1 phase. HHS-induced apoptotic cell death was associated with the up-regulation of pro-apoptotic Bax protein expression, down-regulation of antiapoptotic Bcl-2 protein, and the release of cytochrome c from mitochondria to the cytosol. The treatment of AGS cells with HHS significantly elevated the generation of reactive oxygen species (ROS). Additionally, apoptosis-inducing concentrations of HHS induced the activation of both caspase-9 and -8, initiator caspases of the mitochondrial-mediated intrinsic and death receptor-mediated extrinsic pathways, respectively, and caspase-3, accompanied by proteolytic degradation of poly (ADP-ribose)-polymerase. However, ROS scavenger and pan-caspases inhibitor significantly blocked HHS-induced growth inhibition and apoptosis. Taken together, these findings suggest that HHS induces apoptosis through ROS- and caspase-dependent mechanisms and that HHS may be a potential chemotherapeutic agent for the control of human gastric cancer.

Induction of Apoptosis in Human Colon Carcinoma HCT116 Cells Using a Water Extract of Lepidium virginicum L. (콩다닥냉이 추출물에 의한 HCT116 대장암세포의 사멸 유도에 관한 연구)

  • Chae, Yang-Hui;Shin, Dong-Yeok;Park, Cheol;Lee, Yong-Tae;Moon, Sung-Gi;Choi, Yung-Hyun
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.40 no.5
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    • pp.649-659
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    • 2011
  • To examine the anti-cancer effects of Lepidium virginicum L., the anti-proliferative and pro-apoptotic effects of a water extract of L. virginicum leaves (WELVL) and of L. virginicum roots (WELVR) were investigated in HCT116 human colon carcinoma cells. The treatment of HCT116 cells with WELVL and WELVR resulted in the inhibition of growth and morphological changes in a concentration-dependent manner by inducing apoptosis. The growth inhibition and apoptosis induction by WELVR was stronger than that of WELVL thus, we determined that WELVR was the more optimal extract for this study. The increased apoptotic events in HCT116 cells caused by WELVR were associated with an up-regulation of Fas ligand, Bax, and Bad expression, a down-regulation of Bcl-2, Bcl-$_XL$, and Bid expression, and a decrease in the mitochondrial membrane potential (MMP, ${\Delta}{\psi}m$). WELVR treatment induced the proteolytic activation of caspase-3, -8, and -9, and the degradation of caspase-3 substrate proteins, such as poly (ADP-ribose) polymerase (PARP), ${\beta}$-catenin, and phospholipase C-${\gamma}1$ (PLC-${\gamma}1$). In addition, apoptotic cell death induced by WELVR was correlated with a down-regulation of inhibitors of the apoptosis protein (IAP) family, such as the X-linked inhibitor of apoptosis protein (XIAP), cIAP-1, and cIAP-2. These findings suggest that the WELVR-induced inhibition of cell proliferation is associated with the induction of apoptotic cell death. WELVR may be a potential chemotherapeutic agent for the control of HCT116 human colon carcinoma cells.

Induction of Apoptosis by Ethanol Extracts of Fermented Agabeans in AGS Human Gastric Carcinoma Cells (AGS 인체위암세포에서 발효된 아가콩 추출물에 의한 apoptosis 유도)

  • Kim, Sung-Ryeal;Lee, Hye-Hyeon;Kim, Min-Jeong;Seo, Min-Jeong;Hong, Su-Hyun;Choi, Yung-Hyun;Kang, Byoung-Won;Park, Jeong-Uck;Joo, Woo-Hong;Rhu, Eun-Ju;Jeong, Yong-Kee
    • Journal of Life Science
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    • v.20 no.12
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    • pp.1872-1881
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    • 2010
  • Extracts of soybeans fermented by Bacillus subtilis have a wide variety of functions, such as enhancing the body's immune function, fibrinolysis activity, anti-inflammation, anti-cancer, estrogen function and anti-infection effects. Recently, it was reported that the extracts of fermented beans exhibit strong anti-inflammatory and anti-cancer properties by suppressing the transcription of pro-inflammatory cytokine genes and induction of apoptosis, respectively. However, the mechanisms of their cytotoxicity in human gastric cancer cells are poorly understood. In the present study, we investigated the effects of ethyl alcohol extracts from fermented soybean (FS) and yellow agabean (FYA) on cell growth and apoptosis in AGS human gastric cancer cells. A treatment of FS and FYA inhibited the growth of AGS cells in a concentration-dependent manner by inducing apoptosis. FS- and FYA-induced apoptosis were associated with down-regulation of XIAP and cIAP-2, and up-regulation of pro-apoptotic Bax expression. Moreover, a treatment of FS and FYA not only triggered an increase in the levels of death receptor (DR)4, DR5, Fas and FasL, but also induced the activation of casepase-3, -8 and -9. These findings illustrate that FS and FYA may have a therapeutic potential in human gastric AGS cells and as a functional food.

Effects of Glutamine Deprivation and Serum Starvation on the Growth of Human Umbilical Vein Endothelial Cells (재대정맥 내피세포의 증식에 미치는 글루타민 및 혈청 결핍의 영향)

  • Jeong, Jin-Woo;Lee, Hye Hyeon;Park, Cheol;Kim, Wun-Jae;Choi, Yung Hyun
    • Journal of Life Science
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    • v.23 no.7
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    • pp.926-932
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    • 2013
  • Glutamine and serum are essential for cell survival and proliferation in vitro, yet the signaling pathways that sense glutamine and serum levels in endothelial cells remain uninvestigated. In this study, we examined the effects of glutamine deprivation and serum starvation on the fate of endothelial cells using a human umbilical vein endothelial cell (HUVEC) model. Our data indicated that glutamine deprivation and serum starvation trigger a progressive reduction in cell viability through apoptosis induction in HUVECs as determined by DAPI staining and flow cytometry analysis. Although the apoptotic effects were more predominant in the glutamine deprivation condition, both apoptotic actions were associated with an increase in the Bax/Bcl-2 (or Bcl-xL) ratio, down-regulation of the inhibitor of apoptosis protein (IAP) family proteins, activation of caspase activities, and concomitant degradation of poly (ADP-ribose) polymerases. Moreover, down-regulation of the expression of Bid or up-regulation of truncated Bid (tBid) were observed in cells grown under the same conditions, indicating that glutamine deprivation and serum starvation induce the apoptosis of HUVECs through a signaling cascade involving death-receptor-mediated extrinsic pathways, as well as mitochondria-mediated intrinsic caspase pathways. However, apoptosis was not induced in cells grown in glutamine- and serum-free media when compared with cells exposed to glutamine deprivation or serum starvation alone. Taken together, our data indicate that glutamine deprivation and serum starvation suppress cell viability without apoptosis induction in HUVECs.

Phytochemicals from Goniothalamus griffithii Induce Human Cancer Cell Apoptosis

  • Banjerdpongchai, Ratana;Khaw-on, Patompong;Pompimon, Wialrt
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.7
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    • pp.3281-3287
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    • 2016
  • Bioactive compounds extracted from leaves and twigs of Goniothalamus griffithii include pinocembrin (PCN) and goniothalamin (GTN). The objectives of this study were to investigate the cytotoxic activities of PCN and GTN and their influence on molecular signaling for cell death in several human cancer cell lines compared to normal murine fibroblast NIH3T3 cells. GTN exhibited the most potent cytotoxicity against MCF-7 > HeLa > HepG2 > NIH3T3 cells with $IC_{50}$ values of 7.33, 14.8, 37.1 and $65.4{\mu}M$, respectively, whereas PCN was cytotoxic only to HepG2 cells with $IC_{50}$ values of ${\sim}80{\mu}M$. Apoptotic cell death was confirmed by staining the cells with annexin V-FITC and propidium iodide (PI) employing flow cytometry. Apoptosis was shown by externalization of phosphatidylserine in goniothalamin-treated MCF-7 cells in a dose response manner. Positive PI-stained cells with the typical morphology of apoptotic cells were increased dose-dependently. Furthermore, reduction of mitochondrial transmembrane potential was found in goniothalamin-treated MCF-7, HepG2 and HeLa cells. GTN treatment in MCF-7 increased caspase-3, -8 and -9 activities while GTN-induced HeLa cells showed an increase of both caspase-3 and -9 activities. But an increased caspase-8 activity was demonstrated in GTN- and PCN-treated MCF-7 and HepG2 cells, respectively. Taken together, GTN- and PCN-induced human cancer cell apoptosis was through different molecular mechanisms or signaling pathways, which might be due to different machineries in different types of cancer cells, as evidenced by the compound-modulated caspase activities in both intrinsic and/or extrinsic pathways.

Anticancer Activity of Periplanetasin-5, an Antimicrobial Peptide from the Cockroach Periplaneta americana

  • Kim, In-Woo;Choi, Ra-Yeong;Lee, Joon Ha;Seo, Minchul;Lee, Hwa Jeong;Kim, Mi-Ae;Kim, Seong Hyun;Kim, Iksoo;Hwang, Jae Sam
    • Journal of Microbiology and Biotechnology
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    • v.31 no.10
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    • pp.1343-1349
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    • 2021
  • Cockroaches live in places where various pathogens exist and thus are more likely to use antimicrobial compounds to defend against pathogen intrusions. We previously performed an in silico analysis of the Periplaneta americana transcriptome and detected periplanetasin-5 using an in silico antimicrobial peptide prediction method. In this study, we investigated whether periplanetasin-5 has anticancer activity against the human leukemia cell line K562. Cell growth and survival of K562 cells treated with periplanetasin-5 were decreased in a dose-dependent manner. By using flow cytometric analysis, acridine orange/ethidium bromide (AO/EB) staining and DNA fragmentation, we found that periplanetasin-5 induced apoptotic and necrotic cell death in leukemia cells. In addition, these events were associated with increased levels of the pro-apoptotic proteins Fas and cytochrome c and reduced levels of the anti-apoptotic protein Bcl-2. Periplanetasin-5 induces the cleavage of pro-caspase-9, pro-caspase-8, pro-caspase-3, and poly (ADP-ribose) polymerase (PARP). The above data suggest that periplanetasin-5 induces apoptosis via both the intrinsic and extrinsic pathways. Moreover, caspase-related apoptosis was further confirmed by using the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK), which reversed the periplanetasin-5-induced reduction in cell viability. In conclusion, periplanetasin-5 caused apoptosis in leukemia cells, suggesting its potential utility as an anticancer therapeutic agent.