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Kim, Wan-Sung,Lee, Kwang-Soon,Kim, Ji-Hee,Kim, Chun-Ki,Lee, Gwangsoo,Choe, Jongseon,Won, Moo-Ho,Kim, Tae-Hyoung,Jeoung, Dooil,Lee, Hansoo,Kim, Ji-Yoon,Ae Jeong, Mi,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Y PERGAMON PRESS 2017 FREE RADICAL BIOLOGY AND MEDICINE Vol.112 No.-
<P><B>Abstract</B></P> <P>Ligation of the death receptors for TNF-α, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome <I>c</I> release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-α- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome <I>c</I> spontaneously elevated ROS production. In addition, p53-overexpressing cells accumulated intracellular ROS via cytochrome <I>c</I> release mediated by the BH3-only protein Noxa induction. In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome <I>c</I> release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome <I>c</I> release. These data provide evidence that the FADD/caspase-8/Bid/cytochrome <I>c</I> axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Death receptor ligands produce mitochondrial ROS (mROS) in a caspase-8-dependent manner. </LI> <LI> mROS production requires tBid formation and cytochrome <I>c</I> release. </LI> <LI> The caspase-8/Bid/cytochrome <I>c</I> axis plays a key role in death receptor-mediated mROS generation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Yun, Jung-A,Kim, Joohwan,Baek, Yi-Yong,Park, Wonjin,Park, Minsik,Kim, Suji,Kim, Taesam,Choi, Seunghwan,Jeoung, Dooil,Lee, Hansoo,Won, Moo-Ho,Kim, Ji-Yoon,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeon American Society for Pharmacology and Experimental 2019 Molecular pharmacology Vol.96 No.6
<P>The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation by aminopeptidases B and N, it had a short half-life of 1.2 hours in the serum. Therefore, to increase the stability and potency of the peptide, we designed the modified peptide, N-terminally acetylated RLYE (Ac-RLYE), which had a strongly stabilized half-life of 8.8 hours in serum compared with the original parent peptide. The IC<SUB>50</SUB> value of Ac-RLYE for VEGF-A-induced endothelial cell migration decreased to approximately 37.1 pM from 89.1 pM for the parent peptide. Using a mouse xenograft tumor model, we demonstrated that Ac-RLYE was more potent than RLYE in inhibiting tumor angiogenesis and growth, improving vascular integrity and normalization through enhanced endothelial cell junctions and pericyte coverage of the tumor vasculature, and impeding the infiltration of macrophages into tumor and their polarization to the M2 phenotype. Furthermore, combined treatment of Ac-RLYE and irinotecan exhibited synergistic effects on M1-like macrophage activation and apoptosis and growth inhibition of tumor cells. These findings provide evidence that the N-terminal acetylation augments the therapeutic effect of RLYE in solid tumors via inhibition of tumor angiogenesis, improvement of tumor vessel integrity and normalization, and enhancement of the livery and efficacy of the coadministered chemotherapeutic drugs.</P><P><B>SIGNIFICANCE STATEMENT</B></P><P>The results of this study demonstrate that the N-terminal acetylation of the tetrapeptide RLYE (Ac-RLYE), a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor, significantly improves its serum stability, antiangiogenic activity, and vascular normalizing potency, resulting in enhanced therapeutic effect on solid tumors. Furthermore, the combined treatment of Ac-RLYE with the chemotherapeutic drug, irinotecan, synergistically enhanced its antitumor efficacy by improving the perfusion and delivery of the drug into the tumors and stimulating the conversion of the tumor-associated macrophages to an immunostimulatory M1-like antitumor phenotype.</P>
Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein
Kim, Youngmi,Kim, Kyungjong,Park, Deokbum,Lee, Eunmi,Lee, Hansoo,Lee, Yun-Sil,Choe, Jongseon,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2012 The Journal of biological chemistry Vol.287 No.31
Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect
Kim, Youngmi,Kim, Kyungjong,Lee, Hansoo,Han, Sanghwa,Lee, Yun-Sil,Choe, Jongseon,Kim, Young-Myeong,Hahn, Jang-Hee,Ro, Jai Youl,Jeoung, Dooil Elsevier 2009 european journal of pharmacology Vol.612 No.1
<P><B>Abstract</B></P><P>The role of celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial–mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on <I>in vivo</I> atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.</P>
Kim, Youngmi,Park, Deokbum,Kim, Hyuna,Choi, Munseon,Lee, Hansoo,Lee, Yun Sil,Choe, Jongseon,Kim, Young Myeong,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.51
<P>Cancer/testis antigen <U>ca</U>ncer-associated <U>ge</U>ne (CAGE) is known to be involved in various cellular processes, such as proliferation, cell motility, and anti-cancer drug resistance. However, the mechanism of the expression regulation of CAGE remains unknown. Target scan analysis predicted the binding of microRNA-200b (miR-200b) to CAGE promoter sequences. The expression of CAGE showed an inverse relationship with miR-200b in various cancer cell lines. miR-200b was shown to bind to the 3′-UTR of CAGE and to regulate the expression of CAGE at the transcriptional level. miR-200b also enhanced the sensitivities to microtubule-targeting drugs <I>in vitro</I>. miR-200b and CAGE showed opposite regulations on invasion potential and responses to microtubule-targeting drugs. Xenograft experiments showed that miR-200b had negative effects on the tumorigenic and metastatic potential of cancer cells. The effect of miR-200b on metastatic potential involved the expression regulation of CAGE by miR-200b. miR-200b decreased the tumorigenic potential of a cancer cell line resistant to microtubule-targeting drugs in a manner associated with the down-regulation of CAGE. ChIP assays showed the direct regulation of miR-200b by CAGE. CAGE enhanced the invasion potential of a cancer cell line stably expressing miR-200b. miR-200b exerted a negative regulation on tumor-induced angiogenesis. The down-regulation of CAGE led to the decreased expression of plasminogen activator inhibitor-1, a TGFβ-responsive protein involved in angiogenesis, and VEGF. CAGE mediated tumor-induced angiogenesis and was necessary for VEGF-promoted angiogenesis. Human recombinant CAGE protein displayed angiogenic potential. Thus, miR-200b and CAGE form a feedback regulatory loop and regulate the response to microtubule-targeting drugs, as well as the invasion, tumorigenic potential, and angiogenic potential.</P>
Kim, Youngmi,Kim, Hyuna,Park, Hyunmi,Park, Deokbum,Lee, Hansoo,Lee, Yun Sil,Choe, Jongseon,Kim, Young Myeong,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.40
<P>Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs <I>in vitro</I> and <I>in vivo</I>. TargetScan analysis predicted <I>miR-326</I> as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and <I>miR-326. miR-326</I> decreased the apoptotic effect of anti-cancer drugs, and the <I>miR-326</I> inhibitor increased the apoptotic effect of anti-cancer drugs. <I>miR-326</I> enhanced the invasion and migration potential of cancer cells. The <I>miR-326</I> inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as <I>miR-200b</I>, <I>miR-217</I>, and <I>miR-335. miR-200b</I>, <I>miR-217</I>, and <I>miR-335</I> negatively regulated the expression of <I>miR-326</I> and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted <I>miR-200b</I> and <I>miR-217</I> as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and <I>miR-326</I> acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.</P>