Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells

Park, E H; Koh, Sang Seok; Srisuttee, Ratakorn; Cho, I R; Min, H J; Jhun, Byung Hak; Lee, Y S; Jang, Kyung Lib; Kim, C H; Johnston, Randal N.; Chung, Young Hwa

doi:10.1038/cgt.2008.95

Cited by 18 publications

(19 citation statements)

References 52 publications

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“…Although several lines of evidence indicate that Ras-transformed cells are preferentially susceptible to reovirus through the inactivation of PKR phosphorylation, 2,8 we have recently found that PKR inactivation by Ras activation does not determine reovirus replication in a liver cell expressing hepatitis B virus X, an oncoprotein of the hepatitis B virus. 29 Therefore, we believe that other factors mediated by CUG2 may be involved in reovirus replication. To address this question, we examined whether CUG2 expression depends on p38 MAPK and Figure 4 Activation of Ras is required for reovirus propagation and reovirus-induced cell death.…”

Section: Discussionmentioning

confidence: 96%

“…6,7 There is a strong body of evidence that Ras-transformed cells are preferentially susceptible to reovirus (type 3 Dearing strain) through inactivation of PKR (dsRNAactivated protein kinase) phosphorylation, 8,9 and activation of the oncogenic Ras-signaling pathway enhances reoviral oncolytic targeting in various types of human cancers, 10,11 although our recent study shows that other signaling pathways may also contribute to the susceptibility of a hepatic cancer cell to reoviral replication and oncolysis. 12 Reoviral efficacy has been examined in the treatment of gliomas and other cancers in immunocompetent hosts and has not been shown to produce significant toxicities. 13 These and many other results have led to the current tests of reovirus in several clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

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As we have recently found a novel oncogene, the cancer-upregulated gene 2 (CUG2), which was elevated in a variety of tumor tissues such as the ovary, liver, lung and pancreas, we examined whether reovirus could efficiently induce cytolysis in cancer cells expressing CUG2 and thus be used as a potential cancer therapeutic agent. In this study, we describe experiments in which we use reovirus to treat NIH3T3 cells stably expressing either CUG2 (NIH-CUG2) or vector only (NIH-Vec). NIH-CUG2 cells readily support reoviral proliferation and undergo apoptosis, whereas NIH-Vec cells are highly resistant to reoviral infection and virusinduced apoptosis. This notable result may be explained by the observation that CUG2 expression inhibits PKR activation, leading to reoviral proliferation in nonpermissive NIH3T3 cells. Furthermore, reovirus infection results in almost complete regression of tumorgenic NIH-CUG2 cells in transplanted nude mice. As we found that CUG2 enhances activation of MAPK (ERK, JNK and p38), Src kinase and Ras, we examined whether CUG2 confers reoviral replication independent of the Ras or p38 MAPK signaling pathway. From these experiments we found that either inhibition of p38 MAPK or Ras blocks reoviral proliferation even in the presence of CUG2 but inhibition of ERK, JNK and Src kinase does not, indicating that activation of p38 MAPK and Ras has critical roles in reoviral replication in CUG2-expressing tumor cells. Accordingly, we propose that reovirus can be useful in the treatment of transformed cells expressing CUG2, which is commonly detected in various tumor tissues.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

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“…11,12 Activation of the oncogenic Ras-signaling pathway enhances reoviral oncolysis in various types of human cancers, 11,12 although our recent study shows that other signaling pathways may also contribute to the susceptibility of hepatic cancer cells to reoviral replication and oncolysis. 13 Reoviral efficacy has been examined in the treatment of gliomas in immunocompetent hosts and has not produced significant toxicities.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of HIF-1α by oncolytic reovirus infection independently of VHL and p53

et al. 2010

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Many oncolytic viruses are currently being tested as potential cancer therapeutic agents. To be effective, these viruses must replicate and propagate efficiently through the tumor mass. However, it is possible that the hypoxia that characterizes many tumors may be an obstacle to viral therapy because of its inhibition of viral replication and propagation. We, therefore, decided to test how oncolytic reovirus and its target cells respond to hypoxia. We found that reovirus infection suppresses hypoxia inducible factor (HIF)-1a protein levels (but not transcript abundance) in colon cancer HCT116 cells under CoCl 2 or hypoxia. Reovirus infection was able to reduce HIF-1a levels in both von Hippel Lindau (VHL)À/À renal carcinoma A498 and p53À/À HCT116 cells, indicating that the decrease of HIF-1a mediated by reovirus requires neither VHL nor p53 proteins. However, treatment with the inhibitor MG132 restored HIF-1a levels, suggesting that reovirus-induced HIF-1a decrease needs proteosomal activity. A498 VHLÀ/À cells with constitutive expression of HIF-1a were relatively resistant to reovirus-induced apoptosis when compared with A498 VHL þ / þ cells. However, we found that the use of YC-1 to target HIF-1a promoted reovirus-induced apoptosis in A498 VHLÀ/À cells. Accordingly, we propose that reovirus may be used together with YC-1 as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1a.

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“…However, reovirus also displays striking cytolytic activity in certain types of transformed cells (4,5). Evidence that Ras-transformed cells are preferentially susceptible to reovirus T3D (type 3 Dearling strain) via inactivation of the protective PKR (dsRNA-activated protein kinase) phosphorylation pathway has been reported (6-8) although our study has revealed that Ras activation alone does not enable reovirus to induce oncolysis in hepatocellular cacinoma cells expressing HBX, an oncoprotein of hepatitis B virus (9). Furthermore, the use of reovirus in the treatment of gliomas in immunocompetent hosts and the inoculation of reovirus into the brains of non-human primates have not produced significant toxicities (10), thereby supporting the current tests of reovirus in several clinical trials (11).…”

Section: Introductionmentioning

confidence: 43%

“…Mutations not only in the K-ras proto-oncogene but also in components of the Wnt/ß-catenin signaling pathway are frequently detected in colorectal cancers (31). Although Ras signaling plays a critical role in dictating host cell permissiveness to reovirus (6), other signaling pathways may also contribute susceptibility to reoviral replication and oncolysis (9). Since it has been reported that reovirus efficiently kills many colon cancer cell lines (12) in vitro and in a rodent model in vivo (12,14,25), we wondered whether upregulation of ß-catenin might in some way enhance reovirus replication.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GSK-3β enhances reovirus-induced apoptosis in colon cancer cells

Min

Koh²,

Cho³

et al. 2009

Int J Oncol

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Abstract. Reovirus functions as an oncolytic agent for many types of cancer including colon cancer. Although most studies have emphasized the role of activated Ras signaling in enhancing reoviral oncolysis in susceptible cells, we note that many colon cancers also display elevated ß-catenin. Thus, it is possible that enhanced ß-catenin may augment reoviral susceptibility in colon cancer cells. To explore this hypothesis, HEK293 cells were treated with the glycogen synthase kinase (GSK)-3ß inhibitor LiCl, thereby inducing ß-catenin, followed by reoviral infection. Co-administration with LiCl indeed enhanced cell death compared to reovirus infection alone, but this was not associated with elevated reoviral replication. Similarly, HEK293 cells expressing the Frizzled-1 receptor in Wnt3a-conditioned medium also showed reovirus replication equivalent to that in cells in control medium, further suggesting that up-regulation of ß-catenin does not enhance the replication of reovirus. Instead, we observed that inhibition of GSK-3ß with LiCl decreased reovirus-induced NF-κB activation, leading to accelerated apoptosis via caspase 8 activation. We further found that colon cancer HCT116 cells were sensitized to apoptosis by co-treatment with reovirus and a GSK-3ß inhibitor, AR-A014418. Finally, we identified that inhibition of NF-κB sensitized apoptosis of HEK293 or HCT 116 cells during reovirus infection. Taken together, we propose that inhibition of GSK-3ß sensitizes reovirus-induced apoptosis of colon cancer cells by downregulation of NF-κB activity, offering a potentially improved therapeutic strategy for the treatment of colon cancer.

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Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells

Cited by 18 publications

References 52 publications

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Down-regulation of HIF-1α by oncolytic reovirus infection independently of VHL and p53

Inhibition of GSK-3β enhances reovirus-induced apoptosis in colon cancer cells

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