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

Park, E-H; Park, E H; I-R, Cho; Srisuttee, Ratakorn; Min, H J; Mj, Oh; Yj, Jeong; Jhun, Byung Hak; Johnston, Randal N.; Lee, Soo Jin; Koh, Sang Seok; Chung, Youngjin

doi:10.1038/cgt.2009.83

Cited by 27 publications

(23 citation statements)

References 27 publications

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“…Like RAS mutations, CUG2 expression is associated with inactivation of PKR and activation of the RAS/p38 MAPK signaling pathway (28). We evaluated the role of CUG2 in vitro and in patient samples.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Sborov

Nuovo

Stiff

et al. 2014

Clinical Cancer Research

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Introduction Reolysin®, a proprietary isolate of reovirus Type 3 Dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase 1 – 2 trials; no clinical trials have been conducted in patients with hematologic malignancies. Methodologies A phase 1 trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by In situ based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer up regulated gene 2 (CUG2) were evaluated in patient samples and MM cell lines. Neutralizing Anti-Reovirus Antibody (NARA) assay was performed weekly during cycle 1. Results There were no dose limiting toxicities (DLTs), patients reached the 3 x 1010 TCID50 daily on days 1-5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. In situ hybridization demonstrated reoviral genome confined in MM cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA positive cells. The longest durations of stable disease were 4, 5 and 8 months. Conclusions Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within MM cells. Our data support that in MM cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.

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Section: Discussionmentioning

confidence: 99%

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Sborov

Nuovo

Stiff

et al. 2014

Clinical Cancer Research

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“…As reovirus infection is correlated with RAS, pERK, and apoptosis (analyzed here by caspase-3 and the TUNEL assay), but not with PKR (phosphorylated form) expression, 1,14,15 we next analyzed the percentage of cancer cells positive for these markers in the SK-Mel28 cancer cells unexposed vs exposed to the virus. As evident from Table 1, in each case, there was a significant increase ( P <0.0001) in the percentage of cancer cells that expressed each marker after reovirus treatment.…”

Section: Resultsmentioning

confidence: 99%

“…1,14,15 Thus, we examined a series of the reoviral-positive cancer tissues for the expression of the pERK, PKR, Ras, and p38. When analyzed separately in serial sections it was evident that there was a strong similarity in the distribution of p38, pERK, or Ras when compared with histological distribution of the reoviral protein-positive cells.…”

Section: Resultsmentioning

confidence: 99%

“…13 Park et al 14 showed that NIH 3T3 cells were highly resistant to reovirus but, after stably transfected with the oncogene CUG2, the p38 and Ras were upregulated, and the cancer cells then became highly susceptible to reovirus infection with an associated marked increase in the apoptotic death. It has been well established that p38 expression is a key molecular event in fostering reovirus replication in cancer cells.…”

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confidence: 99%

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Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

et al. 2012

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We analyzed the in situ molecular correlates of infection from cancer patients treated with reovirus. Melanoma, colorectal, and ovarian cancer samples from such patients showed variable infection of the cancer cells but not the intermingled benign cells. RT in situ PCR showed most cancer cells contained the viral genome with threefold less having productive viral infection as documented by either tubulin or reoviral protein co-expression. Productive infection in the cancer cells was strongly correlated with co-expression of p38 and caspase-3 as well as apoptosis-related death (P<0.001). The cancer cell apoptotic death was due to a marked viral-induced inhibition of microRNA-let-7d that, in turn, upregulated caspase-3 activity. In summary, reovirus shows a striking tropism to cancer cells in clinical samples. A rate-limiting factor of reovirus-induced cancer cell death is productive viral infection that operates via the marked reduction of microRNA-let-7d and concomitant elevated caspase-3 expression.

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“…There is a strong body of evidence that Ras-transformed cells are preferentially susceptible to reovirus (type 3 Dearing strain) via inactivation of PKR (dsRNA-activated protein kinase) phosphorylation (15,16). Accordingly, activation of the oncogenic Ras-signaling path-way enhances reoviral oncolytic targeting in various types of human cancers (17)(18)(19), although our recent study shows that other signaling pathways may also contribute to the susceptibility of these cancers to reoviral replication and oncolysis (20). In addition, our study first reports that reovirus infection induces down-regulation of hypoxia-inducible factor (HIF)-1· independently of VHL and p53, suggesting that reovirus may be useful as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1· (21).…”

Section: Introductionmentioning

confidence: 99%

Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation

Cho

Koh²,

Min³

et al. 2010

Int J Oncol

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Abstract. The tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirusmediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the cotreatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells. IntroductionTNF-related apoptosis-inducing ligand (TRAIL), which belongs to the family of TNF, induces apoptosis in a wide variety of tumor cells in vitro and in vivo but does not cause toxicity in a majority of normal cells (1,2). Thus, TRAIL has been suggested as a novel anti-cancer therapeutic drug. The TRAIL-mediated apoptotic signal is transduced through the cell surface death receptor (DR)s such as DR4/TRAIL-R1 and DR5/TRAIL-R2 (3,4). Detailed studies have shown that TRAIL triggers apoptosis by recruiting the initiator procaspase-8 through the adaptor protein FADD. Caspase-8 can directly activate downstream effector caspases including procaspase-3, -6 and -7, or cleave Bid, which triggers mitochondrial damage (5,6). However, different types of cancer cells appear to differ in their sensitivity to TRAIL treatment. Recent studies have reported that prostate and renal cancer cells are resistant to TRAIL treatment due to an up-regulation of Akt activity and enhanced FLIP expression (7,8). In addition, it has been reported that the resistance of certain gastric cancer cells to TRAIL-induced apoptosis can be explained by the up-regulation of FLIPs by Akt, indicating that Akt is a crucial component in the regulation of TRAIL-induced apoptosis (9). In contrast, other studies failed to demonstrate a link between FLIP expression and TRAIL resistance using melanoma and Burkitt's lymphoma (10,11).The human reovirus is a ubiquitous, non-enveloped virus with 10 segments of double-stranded RNA (12). The virus infection is usually restricted to the upper respiratory and gastrointestinal tracts and is often...

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

Cited by 27 publications

References 27 publications

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation

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