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

Cho, I R; Koh, Sang Seok; Min, Hye Jin; Park, E H; Ratakorn, S; Jhun, Byung Hak; Jeong, Sung Hoon; Yoo, Young-Hyun; Youn, Hong Duk; Johnston, Randal N.; Chung, Young Hwa

doi:10.1038/cgt.2009.84

Cited by 33 publications

(29 citation statements)

References 37 publications

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“…The cytotoxic effects of a number of oncolytic viruses are affected by hypoxia and the level of HIF in the infected cells (Cho et al , 2010; Connor et al , 2004; Hiley et al , 2010). Viral infection itself caused deregulation of HIF levels within hypoxic cancer cells (Gupta-Saraf & Miller, 2014), resulting in the varying regulation of their downstream target genes (Cho et al , 2010). In the present study, we showed that a velogenic NDV infection led to a downregulation of HIF-1α protein in a p53-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

Abd‐Aziz

Stanbridge

Shafee

2016

Journal of General Virology

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Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.

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Section: Discussionmentioning

confidence: 99%

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

Abd‐Aziz

Stanbridge

Shafee

2016

Journal of General Virology

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“…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). It has also been reported that reoviral oncolysis was associated with the induction of apoptosis in various cancer types (22).…”

Section: Introductionmentioning

confidence: 79%

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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“…101 They found that reovirus infection suppresses HIF-1α at the protein level, but not at the messenger RNA level, in colon cancer HCT116 cells under hypoxic conditions. This reduction of HIF-1α is independent of VHL or p53 because it took place in both VHL-/-renal carcinoma A498 and p53-/-HCT116 colorectal cancer cells.…”

Section: Reovirusmentioning

confidence: 99%

“…The authors proposed to use reovirus together with an HIF-1α inhibitor as a potential therapeutic regimen against chemoresistant or radioresistant tumors that are hypoxic with increased levels of HIF-1α. 101 As a result, there appears to be a functional similarity between reovirus and VSV in their sensitivity to elevated levels of HIF-1α. 97,101 EMCV Picornaviruses have been explored as OVs.…”

Section: Reovirusmentioning

confidence: 99%

“…101 As a result, there appears to be a functional similarity between reovirus and VSV in their sensitivity to elevated levels of HIF-1α. 97,101 EMCV Picornaviruses have been explored as OVs. Seneca Valley virus-001 is a novel naturally occurring replicating picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer.…”

Section: Reovirusmentioning

confidence: 99%

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The impact of hypoxia on oncolytic virotherapy

Guo¹

2011

VAAT

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Abstract:The hypoxic tumor microenvironment plays significant roles in tumor cell metabolism and survival, tumor growth, and progression. Hypoxia modulates target genes in target cells mainly through an oxygen-sensing signaling pathway mediated by hypoxia-inducible factor of transcription factors. As a result, hypoxic tumor cells are resistant to conventional therapeutics such as radiation and chemotherapy. Oncolytic virotherapy may be a promising novel therapeutic for hypoxic cancer. Some oncolytic viruses are better adapted than others to the hypoxic tumor environment. Replication of adenoviruses from both groups B and C is inhibited, yet replication of herpes simplex virus is enhanced. Hypoxia seems to exert little or no effect on the replication of other oncolytic viruses. Vaccinia virus displayed increased cytotoxicity in some hypoxic cancer cells even though viral protein synthesis and transgene expression were not affected. Vesicular stomatitis virus replicated to similar levels in both hypoxic and normoxic conditions, and is effective for killing hypoxic cancer cells. However, vesicular stomatitis virus and reovirus, but not encephalomyocarditis virus, are sensitive to elevated levels of hypoxia-inducible factor-1α in renal cancer cells with the loss of von Hippel-Lindau tumor suppressor protein, because elevated hypoxia-inducible factor activity confers dramatically enhanced resistance to cytotoxicity mediated by vesicular stomatitis virus or reovirus. A variety of hypoxia-selective and tumor-type-specific oncolytic adenoviruses, generated by incorporating hypoxia-responsive elements into synthetic promoters to control essential genes for viral replication or therapeutic genes, have been shown to be safe and efficacious. Hypoxic tumor-homing macrophages can function effectively as carrier cells to deliver an oncolytic adenovirus to the hypoxic/necrotic areas of the tumor. It is envisioned that further improved oncolytic viruses will be highly effective against hypoxic tumor, especially when combined with other therapeutic regimens such as immunotherapy, radiation therapy, and/or chemotherapy.

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

Cited by 33 publications

References 37 publications

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

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

The impact of hypoxia on oncolytic virotherapy

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