Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Ebert, Daniel H.; Kopecky-Bromberg, Sarah A.; Dermody, Terence S.

doi:10.1074/jbc.m310048200

Cited by 15 publications

(18 citation statements)

References 71 publications

(67 reference statements)

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“…This occurs through the acquisition of a PI or cured cellular state (Taber et al, 1976;Ahmed et al, 1981;Ahmed and Fields, 1982;Danis et al, 1993;Dermody et al, 1993Dermody et al, , 1995Baer and Dermody, 1997;Wetzel et al, 1997;Chappell et al, 1998;Baer et al, 1999;Ebert et al, 2004). The aim of this study was to evaluate the potential limitations that the emergence of PI or cured cells may pose for reovirus oncolytic therapy.…”

Section: Discussionmentioning

confidence: 99%

The oncolytic effect in vivo of reovirus on tumour cells that have survived reovirus cell killing in vitro

et al. 2006

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The use of oncolytic viruses has received considerable attention in recent years and many viruses have proved to be effective against a variety of cancer models and a few are currently being used in clinical trials. However, the possible emergence and outcome of virus-resistant tumour cells has not been addressed. We previously reported the effective use of reovirus against lymphoid malignancies, including the Burkitt's lymphoma cell line Raji. Here we isolated in vitro persistently infected (PI) Raji cells, and cells 'cured' of persistent reovirus infection ('cured' cells). Both PI and cured Raji cells resisted reovirus infection and cell killing in vitro. In vivo, the PI cells were non-tumorigenic in SCID mice, but cured cells regained the parental cells' ability to form tumours. Tumour xenografts from the cured cells, however, were highly susceptible to reovirus oncolysis in vivo. This susceptibility was due to the proteolytic environment within tumours that facilitates reovirus infection and cell killing. Our results show that persistent infection by reovirus impedes tumour development and that although PI cells cleared of reovirus are tumorigenic, they are killed upon rechallenge with reovirus. Both the PI and cured states are therefore not likely to be significant barriers to reovirus oncolytic therapy.

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Section: Discussionmentioning

confidence: 99%

The oncolytic effect in vivo of reovirus on tumour cells that have survived reovirus cell killing in vitro

et al. 2006

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“…Additional insights into the role of cathepsins in necrosis and in the necrotic cleavage of intracellular autoantigens could be obtained in future studies using cathepsin-deficient cell lines and mouse models. Cell lines have been described in which cathepsin L has been genetically knocked out (16), silenced via RNA inhibition (34), or rendered inactive by persistent viral infection (35). In preliminary experiments, we observed that the L929-derived mutant cell line LX, which was obtained by persistent reovirus infection and lacks activity of both cathepsin B and cathepsin L (35), showed a slight delay in TNF␣/Z-VAD-FMK-mediated necrosis and topo I cleavage compared with L929 cells (Pacheco FJ, et al: unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Pacheco¹,

Servin²,

Dang³

et al. 2005

Arthritis & Rheumatism

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Objective. Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation. These autoantibodies recognize topo I and fragments of this autoantigen generated during apoptosis and necrosis. We undertook this study to determine whether lysosomal cathepsins are involved in topo I fragmentation during necrosis.Methods. Topo I cleavage during necrosis was assessed by immunoblotting of lysates from L929 fibroblasts exposed to tumor necrosis factor ␣ (

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“…This is associated with constitutive PKR phosphorylation in the HTR1 cells, which may contribute to the diminished viral replication potential in these cells (Danis et al, 1997;Yeung et al, 1999). A complementary cellular response is the significant reduction of endosomal cathepsin B activity (Figure 7), which is required for efficient reoviral entry into cells (Ebert et al, 2004). Thus it appears likely that these two events (PKR activation and cathepsin B reduction) together can account to a large extent for the presence in the virus-resistant cells of a persistent low-level infection.…”

Section: Discussionmentioning

confidence: 99%

“…Several investigators have shown that endosomal proteases such as cathepsin B and L, which are required for reoviral entry, can be altered in persistently infected cells (Baer et al, 1999;Ebert et al, 2004). We therefore examined cathepsin B and L activity in HT1080 and HTR1 cells using fluorogenic substrates as described in Methods.…”

Section: Htr1 Cells Showed Reduced Cellular Cathepsin B Activitymentioning

confidence: 99%

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

et al. 2007

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Reovirus shows considerable potential as an oncolytic agent for Ras-activated tumors and is currently in clinical trials. Here we ask whether such tumor cell lines can acquire resistance to reoviral oncolysis. We challenged human HT1080 fibrosarcoma cells that carry a Ras mutation by prolonged exposure to reovirus, thereby yielding highly virus-resistant HTR1 cells. These cells are persistently infected with reovirus, exhibit high Ras activity and retain the original Ras gene mutation, showing that resistance to reovirus can be displayed in cells with active Ras. The HTR1 cells also exhibit reduced cellular cathepsin B activity, which normally contributes to viral entry and activation. Persistently infected HTR1 cells were not tumorigenic in vivo, whereas immunologically cured virus-free HTR1 cells were highly tumorigenic. Thus, acquisition of resistance to reovirus may constrain therapeutic strategies. To determine whether reoviral resistance is associated with a general reduction in apoptotic potential, we challenged the HTR1 cells with apoptotic inducers and E1B-defective adenovirus, resulting in significant apoptosis and cell death following both approaches. Therefore, even if resistance to reoviral oncolysis should arise in tumor cells in vivo, other therapeutic strategies may nevertheless remain effective.

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Cathepsin B Is Inhibited in Mutant Cells Selected during Persistent Reovirus Infection

Cited by 15 publications

References 71 publications

The oncolytic effect in vivo of reovirus on tumour cells that have survived reovirus cell killing in vitro

The oncolytic effect in vivo of reovirus on tumour cells that have survived reovirus cell killing in vitro

Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

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