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Kim, Man-Bok,Chung, Young-Hwa,Johnston, Randal N. The Microbiological Society of Korea 2007 The journal of microbiology Vol.45 No.3
REOviruses (Respiratory Enteric Orphan viruses) are ubiquitous, non-enveloped viruses containing 10 segments of double-stranded RNA (dsRNA) as their genome. They are common isolates of the respiratory and gastrointestinal tract of humans but are not associated with severe disease and are therefore considered relatively benign. An intriguing characteristic of reovirus is its innate oncolytic potential, which is linked to the transformed state of the cell. When immortalized cells are transfected in vitro with activated oncogenes such as Ras, Sos, v-erbB, or c-myc, they became susceptible to reovirus infection and subsequent cellular lysis, indicating that oncogene signaling pathways are exploited by reovirus. This observation has led to the use of the virus in clinical trials as an anti-cancer agent against oncogenic tumors. In addition to the exploitation of oncogene signaling, reovirus may further utilize host immune responses to enhance its antitumor activity in vivo due to its innate interferon induction ability. Reovirus is, however, not entirely benign to immunocompromised animal models. Reovirus causes so-called "black feet syndrome" in immunodeficient mice and can also harm neonatal animals. Because cancer patients often undergo immunosuppression due to heavy chemo/radiation-treatments or advanced tumor progression, this pathogenic response may be a hurdle in virus-based anticancer therapies. However, a genetically attenuated reovirus variant derived from persistent reovirus infection of cells in vitro is able to exert potent anti-tumor activity with significantly reduced viral pathogenesis in immunocompromised animals. Importantly, in this instance the attenuated, reovirus maintains its oncolytic potential while significantly reducing viral pathogenesis in vivo.
조일래,정영화,고상석,Hye-Jin Min,Su Jin Kim,이양순,Eun-Hee Park,Srisuttee Ratakorn,전병학,Sangtaek Oh,Randal N. Johnston 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.2
It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies),contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of β-catenin while the suppression of PAUF by shRNA down-regulates β-catenin. The induction of β-catenin by PAUF is mediated by the activities of Akt and GSK-3β, but inhibition of downstream ERK does not reduce β-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of β-catenin, we examined the phosphorylation status of β-catenin in the presence of PAUF compared with that of β-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of β-catenin but no phosphorylation at Ser-45,indicating that a unique phosphorylation pattern of β-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both cyclin-D1 and c-Jun, target genes of β-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of β-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize β-catenin via a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.
KAEWPIBOON, CHUTIMA,SRISUTTEE, RATAKORN,MALILAS, WARAPORN,MOON, JEONG,OH, SANGTAEK,JEONG, HYE GWANG,JOHNSTON, RANDAL N.,ASSAVALAPSAKUL, WANCHAI,CHUNG, YOUNG-HWA SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.11 No.3
<P>Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT???eto) were used and compared with A549 parental cells. A549RT???eto cells demonstrated increased resistance to etoposide???induced apoptosis when compared with A549 parental cells. Notably, A549RT???eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho???Stat1 and P???glycoprotein [P???gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT???eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide???induced apoptosis and reduce expression levels of HDAC4, P???gp and phospho???Stat1. In addition, the suppression of Stat1 with siRNA enhanced etoposide???induced apoptosis and reduced the expression levels of HDAC4 and P???gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P???gp. Notably, TSA treatment reduced P???gp transcript levels but Stat1 siRNA treatment did not, suggesting that P???gp is regulated by HDAC at the transcriptional level and by Stat1 at the post???transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P???gp expression in human A549 lung cancer cells.</P>
Cho, Il-Rae,Koh, Sang-Seok,Min, Hye-Jin,Kim, Su-Jin,Lee, Yang-Soon,Park, Eun-Hee,Ratakorn, Srisuttee,Jhun, Byung-Hak,Oh, Sang-Taek,Johnston, Randal N.,Chung, Young-Hwa Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.2
It is not yet understood how the enhanced expression of pancreatic adenocarcinoma up-regulated factor (PAUF; a novel oncogene identified in our recent studies), contributes to the oncogenesis of pancreatic cells. We herein report that PAUF up-regulates the expression and transcriptional activity of ${\beta}$-catenin while the suppression of PAUF by shRNA down-regulates ${\beta}$-catenin. The induction of ${\beta}$-catenin by PAUF is mediated by the activities of Akt and GSK-$3{\beta}$, but inhibition of downstream ERK does not reduce ${\beta}$-catenin expression. To test whether PAUF emulates either the Wnt3a-mediated or the protein kinase A-mediated signaling pathway for the stabilization of ${\beta}$-catenin, we examined the phosphorylation status of ${\beta}$-catenin in the presence of PAUF compared with that of ${\beta}$-catenin during treatment with Wnt3a or dibutyryl cAMP, a cell permeable cyclic AMP analogue. PAUF expression induces phosphorylation at Ser-33/37/Thr-41 and Ser-675 of ${\beta}$-catenin but no phosphorylation at Ser-45, indicating that a unique phosphorylation pattern of ${\beta}$-catenin is caused by PAUF. Finally, the expression of PAUF up-regulates both $cyclin-D1$ and $c-Jun$, target genes of ${\beta}$-catenin, leading to a rapid proliferation of pancreatic cells; conversely decreased PAUF expression (by shRNA) results in the reduced proliferation of pancreatic cells. Treatment with hexachlorophene (an inhibitor of ${\beta}$-catenin) reduces the proliferation of pancreatic cells despite the presence of PAUF. Taken together, we propose that PAUF can up-regulate and stabilize ${\beta}$-catenin $via$ a novel pattern of phosphorylation, thereby contributing to the rapid proliferation of pancreatic cancer cells.
Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.
Kim, Manbok,Hansen, Kristina K,Davis, Lesley,van Marle, Guido,Gill, Michael John,Fox, Julie D,Hollenberg, Morley D,Rancourt, Derrick E,Lee, Patrick W K,Yun, Chae-Ok,Johnston, Randal N International Medical Press 2010 ANTIVIRAL THERAPY Vol.15 No.6
<P>BACKGROUND: Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy. METHODS: Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors. RESULTS: We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK-treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice. CONCLUSIONS: Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.</P>