Alphavirus M1 induces apoptosis of malignant glioma cells via downregulation and nucleolar translocation of p21WAF1/CIP1 protein

Hu, Jun; Cai, Xiaofeng; Gao, Yan

doi:10.4161/cc.8.20.9832

Cited by 42 publications

(36 citation statements)

References 67 publications

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“…p21 protects cells by upregulating the Nrf2 signaling pathway, 45 and is also implicated in regulation of apoptosis. 46,47 Although p21 is a p53-target protein, the stress-induced and 3 activation and apoptosis. In certain cell types, activation of caspase 8 by curcumin may, thus, initiate the caspase cascade; however, execution of apoptosis appears to be largely dependent on activation of a caspase 9-mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis

et al. 2011

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“…Also, M1 does not cause apparent disease symptoms in mice or rats, even on administration of doses up to 3 × 10 7 pfu per mouse or 3 × 10 8 pfu per rat. Earlier, we reported that M1 induces apoptosis in glioma cells (10). Thus, we hypothesized that an apathogenic cancer cellkilling virus could be a candidate for systemic oncolytic therapy.…”

mentioning

confidence: 95%

“…M1 is a strain of Getah-like alphavirus that was isolated from culicine mosquitoes collected on Hainan Island of China (10,11). Getah virus is transmitted mainly among horses and pigs, and it has not been linked to human illness (12)(13)(14).…”

mentioning

confidence: 99%

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Lin¹,

Zhang²,

Liang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.

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“…The caspase-3/7 flow cytometry assay kit was from Life Technologies (C10427). The strain of M1 virus has been described in our previous research (5,6), and the virus was grown in the Vero cell line. The titer of virus was calculated by median tissue culture infectious dose assay in BHK-21 cell line.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously identified M1, a strain of Getah-like alphavirus isolated from culicine mosquitoes in the Hainan province of China, as an oncolytic virus that induces endoplasmic reticulum (ER) stress-mediated apoptosis in zinc-finger antiviral protein (ZAP)-deficient cancer cells (5,6). Recently, M1 was reported to be nonpathogenic in nonhuman primates after multiple rounds of repeated i.v.…”

mentioning

confidence: 99%

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Cai

Lin

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress-and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.oncolytic virus | SMAC mimetics | bystander killing effect

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Alphavirus M1 induces apoptosis of malignant glioma cells via downregulation and nucleolar translocation of p21WAF1/CIP1 protein

Cited by 42 publications

References 67 publications

Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis

Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

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