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Lee, Hyung-Chahn,Park, In-Chul,Park, Myung-Jin,An, Sungkwan,Woo, Sang-Hyeok,Jin, Hyeon-Ok,Chung, Hee Yong,Lee, Su-Jae,Gwak, Ho-Shin,Hong, Young-Jun,Yoo, Doo-Hyun,Rhee, Chang-Hun,Hong, Seok-Il Wiley Subscription Services, Inc., A Wiley Company 2005 Journal of cellular biochemistry Vol.94 No.3
<P>Non-steroidal anti-inflammatory drug (NSAID), sulindac has chemopreventive and anti-tumorigenic properties, however, the molecular mechanism of this inhibitory action has not been clearly defined. The Akt/protein kinase B, serine/threonine kinase is well known as an important mediator of many cell survival signaling pathways. In the present study, we demonstrate that down-regulation of Akt is a major effect of anti-invasiveness property of sulindac and its metabolites in glioblastoma cells. Myristoylated Akt (MyrAkt) transfected U87MG glioblastoma cells showed increase invasiveness, whereas DN-Akt transfected cells showed decrease invasiveness indicating that Akt potently promoted glioblastoma cell invasion. MMP-2 promoter and enzyme activity were up-regulated in Akt kinase activity dependent manner. Sulindac and its metabolites down-regulated Akt phosphorylation, inhibited MMP-2 production, and significantly inhibited invasiveness of human glioblastoma cells. In addition, sulindac and LY294002, a selective inhibitor of phosphoinositide 3-kinase (PI3K), synergistically inhibited the invasion of glioblastoma cells. Furthermore, only celecoxib showed Akt phosphorylation reduction and an anti-invasivness in glioblastoma cells, whereas aspirin, ketoprofen, ketorolac, and naproxen did not. In conclusion, our results provide evidence that down-regulation of Akt pathway and MMP-2 may be one of the mechanisms by which sulindac and its metabolites inhibit glioblastoma cell invasion. © 2004 Wiley-Liss, Inc.</P>
Park, Myung-Jin,Lee, Jae-Young,Kwak, Hee-Jin,Park, Chang-Min,Lee, Hyung-Chahn,Woo, Sang Hyeok,Jin, Hyun-Ok,Han, Chul-Ju,An, Sungkwan,Lee, Seung-Hoon,Chung, Hee Yong,Park, In-Chul,Hong, Seok-Il,Rhee, C Wiley Subscription Services, Inc., A Wiley Company 2005 Journal of cellular biochemistry Vol.95 No.5
<P>In order to define the role of As<SUB>2</SUB>O<SUB>3</SUB> in regulating the tumor cell invasiveness, the effects of As<SUB>2</SUB>O<SUB>3</SUB> on secretion of matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA), and in vitro invasion of HT1080 human fibrosarcoma cells were examined. As<SUB>2</SUB>O<SUB>3</SUB> inhibited cell adhesion to the collagen matrix in a concentration dependent manner, whereas the same treatment enhanced cell to cell interaction. In addition, As<SUB>2</SUB>O<SUB>3</SUB> inhibited migration and invasion of HT1080 cells stimulated with phorbol 12-myristate 13-aceate (PMA), and suppressed the expression of MMP-2, -9, membrane type-1 MMP, uPA, and uPA receptor (uPAR). In contrast, As<SUB>2</SUB>O<SUB>3</SUB> increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and PA inhibitor (PAI)-1, and reduced the MMP-2, -9, and uPA promoter activity in the presence and absence of PMA. Furthermore, the promoter stimulating and DNA binding activity of nuclear factor-κB (NF-κB) was blocked by As<SUB>2</SUB>O<SUB>3</SUB>, whereas the activator protein-1 activity was unchanged. Pretreatment of the cells with N-acetyl-L-cysteine (NAC) significantly prevented suppression of MMPs and uPA secretion, DNA binding activity of NF-κB, and in vitro invasion of HT1080 cells by As<SUB>2</SUB>O<SUB>3</SUB>, suggesting a role of reactive oxygen species (ROS) in this process. These results suggest that As<SUB>2</SUB>O<SUB>3</SUB> inhibits tumor cell invasion by modulating the MMPs/TIMPs and uPA/uPAR/PAI systems of extracellular matrix (ECM) degradation. In addition, the generation of ROS and subsequent suppression of NF-κB activity by As<SUB>2</SUB>O<SUB>3</SUB> might partly be responsible for the phenomena. Overall, As<SUB>2</SUB>O<SUB>3</SUB> shows potent activity controlling tumor cell invasiveness in vitro. © 2005 Wiley-Liss, Inc.</P>
Seo, Sung-Keum,Jin, Hyeon-Ok,Lee, Hyung-Chahn,Woo, Sang-Hyeok,Kim, Eun-Sung,Yoo, Doo-Hyun,Lee, Su-Jae,An, Sungkwan,Rhee, Chang-Hun,Hong, Seok-Il,Choe, Tae-Boo,Park, In-Chul American Society for Pharmacology and Experimental 2008 Molecular pharmacology Vol.73 No.3
<P>Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. Treatment of cancer cells with HDAC blockers, such as suberoylanilide hydroxamic acid (SAHA), leads to the activation of apoptosis-promoting genes. To enhance proapoptotic efficiency, SAHA has been used in conjunction with radiation, kinase inhibitors, and cytotoxic drugs. In the present study, we show that at the suboptimal dose of 250 muM, sulindac [2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]-acetic acid] significantly enhances SAHA-induced growth suppression and apoptosis of A549 human non-small cell lung cancer cells, primarily via enhanced collapse of the mitochondrial membrane potential, release of cytochrome c, and caspase activation. Furthermore, sulindac/SAHA cotreatment induced marked down-regulation of survivin at both the mRNA and protein levels and stimulated the production of reactive oxygen species (ROS), which were blocked by the antioxidant N-acetyl-l-cysteine. Overexpression of survivin was associated with reduced sulindac/SAHA-induced apoptosis of A549 cells, whereas suppression of survivin levels with antisense oligonucleotides or small interfering RNA further sensitized cells to sulindac/SAHA-induced cell death. Our results collectively demonstrate that sulindac/SAHA-induced apoptosis is mediated by ROS-dependent down-regulation of survivin in lung cancer cells.</P>
Bae, Seunghee,Ha, Tae-Su,Yoon, Youngmin,Lee, Joonyoung,Cha, Hwa Jun,Yoo, Hoesook,Choe, Tae-Boo,Li, Shunhua,Sohn, Insook,Kim, Ji-Young,Kim, Cha-Soon,Jin, Hyeon-Ok,Lee, Hyung-Chahn,Park, In-Chul,Kim, Ch D.A. Spandidos 2008 International journal of molecular medicine Vol.21 No.3
<P>Apoptosis executed by the mammalian caspase family plays a fundamental role in cellular homeostasis. Deregulation of this process is associated with several human diseases. The multimerization of ligand-induced death receptors results in the recruitment of the death inducing signaling complex and autocatalytic activation of initiator caspases, including caspase-8 and -10. However, it is still unclear how initiator caspases trigger and control the early apoptotic signaling pathways, partly because the downstream proteolytic cleavage targets of the initiator caspases are not completely known. Although it is known that a number of proteins are cleaved by various members of the caspase family, the identification of specific cleavage substrates of the initiator caspases 8 and 10, has been hindered by a lack of systematic and broadly applicable strategies for substrate identification. In the present study we constructed a mouse cDNA library and used it to perform a systematic, genome-wide screen for novel in vitro substrates of caspase-8 and -10. From this, we successfully identified six putative caspase substrates, including five novel proteins (ABCF1, AKAP1, CPE, DOPEY1 and GOPC1) that may be targeted specifically by the initiator caspases 8 and 10 during the early stages of apoptosis. These findings may provide useful information for elucidating the apoptotic signaling pathways downstream of the death receptors.</P>
A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.
Woo, Sang Hyeok,An, Sungkwan,Lee, Hyung-Chahn,Jin, Hyeon-Ok,Seo, Sung-Keum,Yoo, Doo-Hyun,Lee, Kee-Ho,Rhee, Chang Hun,Choi, Eui-Ju,Hong, Seok-Il,Park, In-Chul American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.45
<P>The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific role of truncated p23 (Delta p23) in this process and the underlying mechanisms remain to be determined. One such client protein, hTERT, is a telomerase catalytic subunit regulated by several chaperone proteins, including Hsp90 and p23. In the present study, we examined the effects of p23 cleavage on hTERT stability and telomerase activity. Our data showed that overexpression of Delta p23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity. Serine phosphorylation of Hsp90 was significantly reduced in cells expressing high levels of Delta p23 compared with those expressing full-length p23. Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Delta p23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death.</P>