Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma

Zhang, Haipeng; Li, Kai; Lin, Yongcheng; Xing, Fan; Xiao, Xiao; Cai, Jing; Zhu, Wenbo; Liang, Jiankai; Tan, Yaqian; Fu, Liwu; Wang, Fang; Yin, Wei; Lu, Bingzheng; Qiu, Pengxin; Su, Xingwen; Gong, Sitang; Bai, Xuetao; Hu, Jun; Gao, Yan

doi:10.1126/scitranslmed.aam7996

Cited by 59 publications

(51 citation statements)

References 53 publications

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“…The UPR consists of the IRE1‐XBP‐1(s) signaling pathway, the PERK‐eIF2α pathway, and the ATF6 pathway . Previous analyses described that both radiation therapy and VCP inhibitors were able to induce the UPR through activating the IRE1‐XBP‐1(s) signaling pathway and the PERK‐eIF2α pathway, without triggering the ATF6 pathway . Similarly, our results also showed the expression of ATF6 showed no difference when treated with radiation therapy and/or NMS‐873.…”

Section: Discussionsupporting

confidence: 73%

“…n.s., not significant, P > .05 ATF6 pathway. 35,39 Similarly, our results also showed the expression of ATF6 showed no difference when treated with radiation therapy and/or NMS-873. Furthermore, our analysis indicated VCP inhibitor has a synergistic effect with radiation therapy.…”

Section: Discussionsupporting

confidence: 72%

“…Valosin-containing protein inhibitors in combination with oncolytic virus M1 was a promising treatment for hepatocellular carcinoma. 35 Bastola et al described the preclinical activity of VCP inhibitors in ovarian cancer cells, and final outcomes showed that VCP inhibitors were able to induce ER stress, cause cell cycle arrest, and trigger caspase-mediated cell death. Thus, VCP inhibitor can be used as a single agent or combined with other antitumor compounds.…”

Section: Discussionmentioning

confidence: 99%

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Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

et al. 2019

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Overcoming resistance to radiation is a great challenge in cancer therapy. Here, we highlight that targeting valosin‐containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

et al. 2019

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“…Pharmacological agents may conditionally enhance oncolytic viral efficacy in destroying malignancies without harming normal tissues. Small-molecule valosin-containing protein inhibitors cooperate with M1 virus by suppressing the IRE1α-XBP1 pathway and promoting irresolvable ER stress to kill HCC cells (211). This study also presented the favorable outcomes of this combinatorial therapeutic strategy in nonhuman primates, encouraging the rapid clinical translation of such therapies.…”

Section: Current and Potential Therapies For The Treatment Of Hccmentioning

confidence: 73%

Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease

Lebeaupin

Vallée

Hazari

et al. 2018

Journal of Hepatology

699

562

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The global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention.

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“…M1 showed high tumor cell selectivity and tumor-killing activity during in vitro and in vivo experiments [73]. Moreover, its antitumor activity can be considerably increased by targeted inhibitors, such as valosin-containing protein (VCP) inhibitor and DNA-dependent kinase (DNA-PK) inhibitor [74,75], suggesting that combining M1 with these inhibitors is an important strategy.…”

Section: Wild-type Ovs In Oncolytic Virotherapymentioning

confidence: 99%

Development of oncolytic virotherapy: from genetic modification to combination therapy

et al. 2020

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Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies.

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Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma

Cited by 59 publications

References 53 publications

Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease

Development of oncolytic virotherapy: from genetic modification to combination therapy

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