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SHIN, DONG YEOK,KIM, GI-YOUNG,KIM, CHAN GIL,KIM, WUN-JAE,KANG, HO SUNG,CHOI, YUNG HYUN Spandidos Publications 2012 ONCOLOGY REPORTS Vol.28 No.3
<P>The DNA methyltransferase inhibitor decitabine, 5-Aza-2'-deoxycytidine, possesses anti-metabolic and anticancer activities in various cancer cells. However, the biochemical mechanisms underlying decitabine-induced inhibition of invasiveness and metastasis have not been thoroughly studied. In this study, we investigated the effect of decitabine on the correlation between tightening of tight junctions (TJs) and anti-invasive activity in AGS human gastric cancer cells. Our data indicated that the inhibitory effects of decitabine on cell motility and invasiveness were associated with increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance (TER). Immunoblotting results indicated that decitabine repressed the levels of the claudin proteins, major components of TJs that play a key role in the control and selectivity of paracellular transport. Furthermore, matrix metalloproteinase (MMP)-2 and -9 activity in the AGS cells was dose-dependently inhibited by treatment with decitabine, and this was correlated with a decrease in mRNA and protein expression. In addition, these effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway in AGS cells. In conclusion, this study suggests that TJs and MMPs are critical targets of decitabine-induced inhibition of invasiveness in AGS human gastric cancer cells.</P>
Dong Yeok Shin,Chi Young Jung,Dong Hoon Kim,Gi Young Kim,강호성,류충호,Soon Chan Hong,Sung Chul Shin,최영현,이원섭,Jing Nan Lu,정진명,Woo Song Ha 대한암예방학회 2009 Journal of cancer prevention Vol.14 No.4
Anthocyanins belong to a class of flavonoids, exhibiting some of the anti-tumor activities: antiangiogenesisand anti-invasive activity. Recently, the anthocyanins from the Fruit of Vitis coignetiae Pulliat(Meoru in Korea, AIMs) have been reported to have anti-cancer activities. Here, we tested the anti-cancereffects of AIMs in human hepatocelluar carcinoma cells (Hep3B and HepG2 cells). The AIMs inhibitedthe proliferation of the cells in a dose dependent manner. Hep3B cells were more sensitive to AIMs. The AIMs induced apoptosis through the loss of MMP (ΔΨm). The AIMs inhibited the motility andinvasion of the cells in wound healing test and Matrigel-invasion assay, respectively. The anti-migratoryand anti-invasive activities of AIMs were superior to the anthocyanins isolated from black bean. Inconclusion, this study indicates that AIMs have apoptotic and anti-invasive effects on human hepatocellularcarcinoma cells. AIMs had stronger anti-invasive activity than the anthocyanins from coat of black beanon both Hep3B and HepG2 cells. This study provides evidence that the anthocyanins isolated from Meorumight be useful in the treatment of human hepatocelluar carcinoma.
흑마늘 추출물이 인체위암세포의 tight junction 투과성 조절과 세포 침윤성 억제에 미치는 영향
Dong Yeok Shin(신동역),Moo Kyoung Yoon(윤무경),Young-Whan Choi(최영환),Oh-Cheon Gweon(권오천),Jung-In Kim(김정인),Tae Hyun Choi(최태현),Yung Hyun Choi(최영현) 한국생명과학회 2010 생명과학회지 Vol.20 No.4
본 연구에서는 흑마늘 열수 추출물(ABG)의 암세포 전이억제 효능을 검정하였다. AGS AGS 인체위암세포의 이동성과 침윤성을 억제하였으며, 이는 TER의 증가와 연관성이 있었다. 또한 ABG에 의한 AGS 위암세포의 침윤성 억제는 TIMPs 발현 증가에 의한 MMPs의 발현 및 활성 저하에 의한 것임을 알 수 있었다. 아울러 AGS 위암세포에서 과발현을 나타내는 TJ 단백질인 claudins의 발현 저하 등이 ABG의 항전이 효과에 연관되어 있음을 알 수 있었다. 이상의 결과는 흑마늘 열수 추출물이 단순한 암세포의 증식억제를 통한 암예방 및 항암활성 뿐만 아니라 암세포의 전이 또한 효과적으로 억제할 수 있음을 보여주며, 이와 연관된 보다 구체적인 분자세포생물학적 접근 및 in vivo 연구의 필요성이 요구됨을 의미한다. Garlic (Allium sativum) has been well-known as a folk remedy for a variety of ailments since ancient times, and it is well documented that enhanced garlic consumption leads to a decrease in incidences of cancer. Tight junctions (TJs) are critical structures for the maintenance of cellular polarity, acting as paracellular permeability barriers and playing an essential role in regulating the diffusion of fluid, electrolytes and macromolecules through the paracellular pathway. Matrix metalloproteinases (MMPs) have been implicated as possible mediators of invasiveness and metastasis in some cancers. In this study, we investigated the potential effects of water extract of aged black garlic (ABG) on the correlation between tightening of TJs and anti-invasive activity in human gastric carcinoma AGS cells. The inhibitory effects of ABG on cell motility and invasiveness were found to be associated with increased tightness of TJs, which was demonstrated by an increase in transepithelial electrical resistance. Additionally, the activities of MMP-2 and -9 in AGS cells were inhibited by treatment with ABG, and this was also correlated with a decrease in the expression of their mRNA and proteins. Furthermore, RT-PCR and immunoblotting results indicated that ABG repressed the levels of the claudin proteins, major components of TJs that playa key role in the control and selectivity of paracellular transport. In conclusion, these results suggest that ABG treatment may inhibit tumor metastasis and invasion, and therefore may act as a dietary source to decrease the risk of developing cancer.
Shin, Dong Yeok,Cha, Hee-Jae,Kim, Gi-Young,Kim, Wun-Jae,Choi, Yung Hyun Molecular Diversity Preservation International (MD 2013 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.14 No.10
<P>Diallyl trisulfide (DATS), an organosulfur compound in garlic, possesses pronounced anti-cancer potential. However, the anti-invasive mechanism of this compound in human bladder carcinoma is not fully understood. In this study, we evaluated the anti-invasive effects of DATS on a human bladder carcinoma (5637) cell line and investigated the underlying mechanism. The results indicated that DATS suppressed migration and invasion of 5637 cells by reducing the activities and expression of matrix metalloproteinase (MMP)-2 and MMP-9 at both the protein and mRNA levels. DATS treatment up-regulated expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in 5637 cells. The inhibitory effects of DATS on invasiveness were associated with an increase in transepithelial electrical resistance and repression of the levels of claudin family members. Although further studies are needed, our data demonstrate that DATS exhibits anti-invasive effects in 5637 cells by down-regulating the activity of tight junctions and MMPs. DATS may have future utility in clinical applications for treating bladder cancer.</P>
Induction of Apoptosis and Inhibition of Invasion in Human Hepatoma Cells by Anthocyanins from Meoru
Shin, Dong Yeok,Ryu, Chung Ho,Lee, Won Sup,Kim, Dong Chul,Kim, Seok Hyun,Hah, Young-Sool,Lee, Sung Joong,Shin, Sung Chul,Kang, Ho Sung,Choi, Yung Hyun Wiley (Blackwell Publishing) 2009 Annals of the New York Academy of Sciences Vol.1171 No.1
<P>Anthocyanins belong to a class of flavonoids exhibiting antioxidant and anti-inflammatory actions as well as a variety of chemotherapeutic effects. However, little is known about the cellular and molecular mechanism of anticancer activity. In this study, we investigated if the anthocyanins (delphinidin-3,5-diglucoside: cyanidin-3,5-diglucoside: petunidin-3,5-diglucoside: delphinidin-3-glucoside: malvdin-3,5-diglucoside: peonidin-3,5-diglucoside: cyanidin-3-glucoside: petunidin-3-glucoside: peonidin-3- glucoside: malvidin-3- glucoside = 27: 63: 8.27: 1:2.21: 6.7: 1.25: 5.72: 1.25) isolated from meoru (Vitis coignetiae Pulliat) exerted antiproliferative and anti-invasive and apoptotic effects on human hepatoma Hep3B cells. It was found that the anthocyanins could inhibit cell growth by 75% at the concentration of 400 microg/mL for 48 h. Flow cytometric analysis showed that the anthocyanins increased the amount of DNA fragments (sub-G1 fraction) in a dose-dependent manner, which is closely related to mitochondrial dysfunction and reduction in antiapoptotic proteins (Bcl-2, xIAP, cIAP-1, and cIAP-2). The anthocyanins also significantly inhibited the migration and invasion of Hep3B cells through a matrigel-coated chamber. Taken together this study indicates that the anthocyanins from meoru have antiproliferative and anti-invasive effects and may induce apoptosis through the activation of the mitochondrial pathway and inhibition of antiapoptotic proteins. This study provides evidence that the anthocyanins isolated from meoru might be useful in the treatment of human hepatitis B-associated hepatoma.</P>
Shin, Dong Yeok,Kim, Gi-Young,Lee, Jun Hyuk,Choi, Byung Tae,Yoo, Young Hyun,Choi, Yung Hyun Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.11
<P>Diallyl disulfide (DADS), a sulfur compound derived from garlic, has various biological properties, such as anticancer, antiangiogenic and anti-inflammatory effects. However, the mechanisms of action underlying the compound’s anticancer activity have not been fully elucidated. In this study, the apoptotic effects of DADS were investigated in DU145 human prostate carcinoma cells. Our results showed that DADS markedly inhibited the growth of the DU145 cells by induction of apoptosis. Apoptosis was accompanied by modulation of Bcl-2 and inhibitor of apoptosis protein (IAP) family proteins, depolarization of the mitochondrial membrane potential (MMP, <I>ΔΨm</I>) and proteolytic activation of caspases. We also found that the expression of death-receptor 4 (DR4) and Fas ligand (FasL) proteins was increased and that the level of intact Bid proteins was down-regulated by DADS. Moreover, treatment with DADS induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular-signal regulating kinase (ERK), p38 MAPK and c-Jun <I>N</I>-terminal kinase (JNK). A specific JNK inhibitor, SP600125, significantly blocked DADS-induced-apoptosis, whereas inhibitors of the ERK (PD98059) and p38 MAPK (SB203580) had no effect. The induction of apoptosis was also accompanied by inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt and the PI3K inhibitor LY29004 significantly increased DADS-induced cell death. These findings provide evidence demonstrating that the proapoptotic effect of DADS is mediated through the activation of JNK and the inhibition of the PI3K/Akt signaling pathway in DU145 cells.</P>
Shin, Dong Yeok,Lu, Jing Nan,Kim, Gi-Young,Jung, Jin Myung,Kang, Ho Sung,Lee, Won Sup,Choi, Yung Hyun National Hellenic Research Foundation 2011 ONCOLOGY REPORTS Vol.25 No.2
<P>Claudins are a family of proteins that are the most important components of the tight junctions. Recently it has been reported that these proteins are overexpressed in cancers and there is a positive correlation between suppression of the expression of these proteins and anti-invasive activity. Matrix metalloproteinases (MMPs) have been implicated as important mediators in cancer invasion. Here, we investigated the effects of anthocyanins on tight junctions (TJs) and the expression of claudins as well as MMPs. The inhibitory effects of the anthocyanins on cell proliferation, motility and invasiveness were found to be associated with tightening TJs, which was demonstrated by an increase in transepithelial electrical resistance (TER). The expression of claudin proteins was suppressed by anthocyanins. Furthermore, the activities of MMP-2 and -9 were dose-dependently suppressed by anthocyanin treatment. These effects were related to activation of 38-MAPK and suppression of the PI3K/Akt pathway in HCT-116 human colon cancer cells.</P>
Shin, Dong Yeok,Park, You-Soo,Yang, Kwangmo,Kim, Gi-Young,Kim, Wun-Jae,Han, Min Ho,Kang, Ho Sung,Choi, Yung Hyun Lychnia 2012 International journal of oncology Vol.41 No.3
<P>The DNA methyltransferase inhibitor decitabine, 5-aza-2'-deoxycytidine, has been found to exert anti-metabolic and anticancer activities when tested against various cultured cancer cells. Furthermore, decitabine has been found to play critical roles in cell cycle arrest and apoptosis in various cancer cell lines; however, these roles are not well understood. In this study, we investigated decitabine for its potential anti-proliferative and apoptotic effects in human leukemia cell lines U937 and HL60. Our results indicated that treatment with decitabine resulted in significantly inhibited cell growth in a concentration- and time-dependent manner by the induction of apoptosis. Decitabine-induced apoptosis in U937 and HL60 cells was correlated with the downregulation of anti-apoptotic Bcl-2, XIAP, cIAP-1 and cIAP-2 protein levels, the cleavage of Bid proteins, the activation of caspases and the collapse of mitochondrial membrane potential (MMP). However, apoptosis induced by decitabine was attenuated by caspase inhibitors, indicating an important role for caspases in decitabine responses. The data further demonstrated that decitabine increased intracellular reactive oxygen species (ROS) generation. Moreover, N-acetyl-L-cysteine, a widely used ROS scavenger, effectively blocked the decitabine-induced apoptotic effects via inhibition of ROS production and MMP collapse. These observations clearly indicate that decitabine-induced ROS in human leukemia cells are key mediators of MMP collapse, which leads to apoptosis induction followed by caspase activation.</P>