Systemically Administered Reovirus-Induced Downregulation of Hypoxia Inducible Factor-1α in Subcutaneous Tumors

Overview

Journal Mol Ther Oncolytics

Publisher Cell Press

Date 2019 Feb 22

PMID 30788427

Citations 10

Authors

Takuma Hotani

Hiroyuki Mizuguchi

Fuminori Sakurai

Affiliations

Soon will be listed here.

Abstract

Reovirus, which possesses a 10-segmented double-stranded RNA genome, mediates superior antitumor effects via not only virus replication in a tumor cell-specific manner but also other mechanisms distinct from virus replication. Several groups, including ours, reported the reovirus-mediated downregulation of hypoxia inducible factor-1α (HIF-1α) following infection in cultured tumor cells; however, it remained to be clarified whether reovirus downregulates the expression of HIF-1α and its target genes in tumor-bearing hosts. We found that reovirus induced significant downregulation of protein levels of HIF-1α and its target genes in the subcutaneous tumors at 120 h post-systemic administration. Expression of reovirus capsid protein σ3 was found in the pimonidazole-positive hypoxic area in the tumor. Significant levels of tumor cell apoptosis were not found in the tumors of reovirus-treated mice at this time point, suggesting that reovirus-mediated tumor cell killing did not largely contribute to the downregulation of HIF-1α protein levels in the tumors. UV-inactivated reovirus did not induce downregulation of HIF-1α expression in the tumors, indicating that virus replication was indispensable for downregulation of HIF-1α expression in the subcutaneous tumors. This study provides important information for the development of reovirus-mediated virotherapy against various types of tumors.

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References

Ravi R, Mookerjee B, Bhujwalla Z, Sutter C, Artemov D, Zeng Q . Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000; 14(1):34-44. PMC: 316350. View

Carmeliet P, Jain R . Angiogenesis in cancer and other diseases. Nature. 2000; 407(6801):249-57. DOI: 10.1038/35025220. View

Comerford K, Wallace T, Karhausen J, Louis N, Montalto M, Colgan S . Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002; 62(12):3387-94. View

Yoo Y, Oh S, Park E, Cho H, Lee N, Park H . Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway. J Biol Chem. 2003; 278(40):39076-84. DOI: 10.1074/jbc.M305101200. View

Wakisaka N, Kondo S, Yoshizaki T, Murono S, Furukawa M, Pagano J . Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 alpha. Mol Cell Biol. 2004; 24(12):5223-34. PMC: 419879. DOI: 10.1128/MCB.24.12.5223-5234.2004. View

Cai Q, Lan K, Verma S, Si H, Lin D, Robertson E . Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions. J Virol. 2006; 80(16):7965-75. PMC: 1563785. DOI: 10.1128/JVI.00689-06. View

Harada H, Kizaka-Kondoh S, Itasaka S, Shibuya K, Morinibu A, Shinomiya K . The combination of hypoxia-response enhancers and an oxygen-dependent proteolytic motif enables real-time imaging of absolute HIF-1 activity in tumor xenografts. Biochem Biophys Res Commun. 2007; 360(4):791-6. DOI: 10.1016/j.bbrc.2007.06.149. View

Nasimuzzaman M, Waris G, Mikolon D, Stupack D, Siddiqui A . Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor. J Virol. 2007; 81(19):10249-57. PMC: 2045478. DOI: 10.1128/JVI.00763-07. View

Errington F, Steele L, Prestwich R, Harrington K, Pandha H, Vidal L . Reovirus activates human dendritic cells to promote innate antitumor immunity. J Immunol. 2008; 180(9):6018-26. DOI: 10.4049/jimmunol.180.9.6018. View

10.

Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel A, Nizet V . NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008; 453(7196):807-11. PMC: 2669289. DOI: 10.1038/nature06905. View

11.

Prestwich R, Errington F, Ilett E, Morgan R, Scott K, Kottke T . Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin Cancer Res. 2008; 14(22):7358-66. PMC: 2701231. DOI: 10.1158/1078-0432.CCR-08-0831. View

12.

Cho I, Koh S, Min H, Park E, Ratakorn S, Jhun B . Down-regulation of HIF-1alpha by oncolytic reovirus infection independently of VHL and p53. Cancer Gene Ther. 2010; 17(5):365-72. DOI: 10.1038/cgt.2009.84. View

13.

Gujar S, Marcato P, Pan D, Lee P . Reovirus virotherapy overrides tumor antigen presentation evasion and promotes protective antitumor immunity. Mol Cancer Ther. 2010; 9(11):2924-33. DOI: 10.1158/1535-7163.MCT-10-0590. View

14.

Wang Y, Liu Y, Malek S, Zheng P, Liu Y . Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011; 8(4):399-411. PMC: 3084595. DOI: 10.1016/j.stem.2011.02.006. View

15.

Adair R, Roulstone V, Scott K, Morgan R, Nuovo G, Fuller M . Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Sci Transl Med. 2012; 4(138):138ra77. PMC: 3893925. DOI: 10.1126/scitranslmed.3003578. View

16.

Figova K, Hrabeta J, Eckschlager T . Anticancer efficiency of reovirus in normoxia and hypoxia. Folia Biol (Praha). 2013; 59(2):68-75. View

17.

Miest T, Cattaneo R . New viruses for cancer therapy: meeting clinical needs. Nat Rev Microbiol. 2013; 12(1):23-34. PMC: 4002503. DOI: 10.1038/nrmicro3140. View

18.

Gupta-Saraf P, Miller C . HIF-1α downregulation and apoptosis in hypoxic prostate tumor cells infected with oncolytic mammalian orthoreovirus. Oncotarget. 2014; 5(2):561-74. PMC: 3964229. DOI: 10.18632/oncotarget.1767. View

19.

Noman M, Desantis G, Janji B, Hasmim M, Karray S, Dessen P . PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014; 211(5):781-90. PMC: 4010891. DOI: 10.1084/jem.20131916. View

20.

Macintyre A, Gerriets V, Nichols A, Michalek R, Rudolph M, Deoliveira D . The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014; 20(1):61-72. PMC: 4079750. DOI: 10.1016/j.cmet.2014.05.004. View