Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Puhlmann, J; Puehler, Florian; Mumberg, Dominik; Boukamp, Petra; Beier, Rudolf

doi:10.1038/onc.2009.507

Cited by 56 publications

(59 citation statements)

References 41 publications

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“…NDV replication has been linked to defects in the antiviral response of cancer cells. However, in our previous studies and other recent studies, many cancer cell lines have been shown to have a functional and intact IFN response after NDV infection (20,28,45,49). To detect IFN induction in A549-neo and A549-Bcl-xL cells and to demonstrate that the IFN produced inhibits NDV replication, we performed the IFN induction bioassay (Fig.…”

Section: Expression Of Influenza Virus Ns1 Protein By Ndv Delays Apopmentioning

confidence: 99%

Oncolytic Specificity of Newcastle Disease Virus Is Mediated by Selectivity for Apoptosis-Resistant Cells

Mansour

Palese

Zamarin

2011

J Virol

126

111

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Newcastle disease virus (NDV) is a negative-sense RNA virus that has been shown to possess oncolytic activity. NDV's selective replication in tumor cells has been previously suggested to be due to the lack of a proper antiviral response in these cells. Here we demonstrate that NDV possesses oncolytic activity in tumor cells capable of a robust type I interferon (IFN) response, suggesting that another mechanism underlies NDV's tumor specificity. We show that the oncolytic selectivity of NDV for tumor cells is dependent upon tumor cell resistance to apoptosis. Utilizing the human non-small-cell lung cancer cell line A549 overexpressing the antiapoptotic protein Bcl-xL, we show significant enhancement of oncolytic activity and NDV replication. Interestingly, while the Bcl-xL-overexpressing cells were resistant to apoptotic stimuli induced by chemotherapeutic agents and early viral replication, during the subsequent viral cycles, we observed a paradoxical increase in apoptosis in response to NDV. The increased oncolytic activity seen was secondary to enhanced viral replication and syncytium formation. The induction of a type I IFN response was enhanced in Bcl-xL cells. Overall, these findings propose a new mechanism for cancer cell specificity for NDV, making it an attractive anticancer agent for chemoresistant tumors with enhanced antiapoptotic activity.

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Section: Expression Of Influenza Virus Ns1 Protein By Ndv Delays Apopmentioning

confidence: 99%

Oncolytic Specificity of Newcastle Disease Virus Is Mediated by Selectivity for Apoptosis-Resistant Cells

Mansour

Palese

Zamarin

2011

J Virol

126

111

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“…Interestingly, for the oncolytic Newcastle disease virus (NDV), Rac1 expression was reported to be sufficient to render non-tumorigenic cells susceptible to NDV replication which identified Rac1 as a potential oncogene. 234 …”

Section: Transformationmentioning

confidence: 99%

Rho’ing in and out of cells

2014

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These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

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“…NDV also encounters a range of antiviral responses, which are proposed to depend on the protein kinase R (PKR)-induced PKR/eIF2a signalling cascade and sequestosome 1 (SQSTM1)-mediated selective degradation of mitochondria by autophagy, called 'mitophagy' (Meng et al, 2014;Zhang et al, 2014). Meanwhile, there is increasing evidence suggesting that other classes of genes, such as the interferon-inducible protein ISG12a and IFNgamma-signalling mediator Rac1, are also involved in virus-host interactions (Liu et al, 2014;Puhlmann et al, 2010). In addition to hosts, viruses, such as herpes simplex virus 1 (HSV-1) (Mostafa et al, 2013), human cytomegalovirus (HCMV) (Cantrell & Bresnahan, 2005), influenza virus (IV) (Goodman et al, 2011) and others (Saribas et al, 2014;Stracker et al, 2004;Trobaugh et al, 2014), regulate host and viral genes to enhance viral replication.…”

mentioning

confidence: 99%

Expression of Raf kinase inhibitor protein is downregulated in response to Newcastle disease virus infection to promote viral replication

Yin

Liu

et al. 2015

Journal of General Virology

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Newcastle disease virus (NDV) causes a severe and economically significant disease affecting almost the entire poultry industry worldwide. However, factors that affect NDV replication in host cells are poorly understood. Raf kinase inhibitory protein (RKIP) is a physiological inhibitor of c-RAF kinase and NF-kB signalling, known for their functions in the control of immune response as well as tumour invasion and metastasis. In the present study, we investigated the consequences of overexpression of host RKIP during viral infection. We demonstrate that NDV infection represses RKIP expression thereby promoting virus replication. Experimental upregulation of RKIP in turn acts as a potential antiviral defence mechanism in host cells that restricts NDV replication by repressing the activation of Raf/MEK/ERK and IkBa/NF-kB signalling pathways. Our results not only extend the concept of linking NDV-host interactions, but also reveal RKIP as a new class of protein-kinase-inhibitor protein that affects NDV replication with therapeutic potential.

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Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Cited by 56 publications

References 41 publications

Oncolytic Specificity of Newcastle Disease Virus Is Mediated by Selectivity for Apoptosis-Resistant Cells

Oncolytic Specificity of Newcastle Disease Virus Is Mediated by Selectivity for Apoptosis-Resistant Cells

Rho’ing in and out of cells

Expression of Raf kinase inhibitor protein is downregulated in response to Newcastle disease virus infection to promote viral replication

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