Down-regulation of HIF-1α by oncolytic reovirus infection independently of VHL and p53

Many oncolytic viruses are currently being tested as potential cancer therapeutic agents. To be effective, these viruses must replicate and propagate efficiently through the tumor mass. However, it is possible that the hypoxia that characterizes many tumors may be an obstacle to viral therapy because of its inhibition of viral replication and propagation. We, therefore, decided to test how oncolytic reovirus and its target cells respond to hypoxia. We found that reovirus infection suppresses hypoxia inducible factor (HIF)-1α protein levels (but not transcript abundance) in colon cancer HCT116 cells under CoCl(2) or hypoxia. Reovirus infection was able to reduce HIF-1α levels in both von Hippel Lindau (VHL)-/- renal carcinoma A498 and p53-/- HCT116 cells, indicating that the decrease of HIF-1α mediated by reovirus requires neither VHL nor p53 proteins. However, treatment with the inhibitor MG132 restored HIF-1α levels, suggesting that reovirus-induced HIF-1α decrease needs proteosomal activity. A498 VHL-/- cells with constitutive expression of HIF-1α were relatively resistant to reovirus-induced apoptosis when compared with A498 VHL+/+ cells. However, we found that the use of YC-1 to target HIF-1α promoted reovirus-induced apoptosis in A498 VHL-/- cells. Accordingly, we propose that reovirus may be used together with YC-1 as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1α. Cancer Gene Therapy (2010) 17, 365-372; doi:10.1038/cgt.2009.84; published online 15 January 2010Park EH, 2009, CANCER GENE THER, V16, P453, DOI 10.1038/cgt.2008.95Cheng J, 2007, CELL, V131, P584, DOI 10.1016/j.cell.2007.08.045Sun HL, 2007, ONCOGENE, V26, P3941, DOI 10.1038/sj.onc.1210169Kim M, 2007, J MICROBIOL, V45, P187Kim HY, 2007, EXP CELL RES, V313, P1866, DOI 10.1016/j.yexcr.2007.03.009Liu YV, 2007, MOL CELL, V25, P207, DOI 10.1016/j.molcel.2007.01.001Hwang IIL, 2006, J VIROL, V80, P10712, DOI 10.1128/JVI.01014-06Roe JS, 2006, MOL CELL, V22, P395, DOI 10.1016/j.molcel.2006.04.006Kong XG, 2006, MOL CELL BIOL, V26, P2019, DOI 10.1128/MCB.26.6.2019-2028.2006Dang DT, 2006, CANCER RES, V66, P1684, DOI 10.1158/0008-5472.CAN-05-2887Escuin D, 2005, CANCER RES, V65, P9021, DOI 10.1158/0008-5472.CAN-04-4095Norman KL, 2005, DRUG DISCOV TODAY, V10, P847Yang WQ, 2004, CLIN CANCER RES, V10, P8561Ikeda Y, 2004, AURIS NASUS LARYNX, V31, P407, DOI 10.1016/j.anl.2004.07.003Norman KL, 2004, P NATL ACAD SCI USA, V101, P11099Stoeltzing O, 2004, J NATL CANCER I, V96, P946, DOI 10.1093/jnci/djh168Brown JM, 2004, NAT REV CANCER, V4, P437, DOI 10.1038/nrc1367Wakisaka N, 2004, MOL CELL BIOL, V24, P5223, DOI 10.1128/MCB.24.12.5223-5234.2004Bardos JI, 2004, BIOESSAYS, V26, P262, DOI 10.1002/bies.20002Yoo YG, 2003, J BIOL CHEM, V278, P39076, DOI 10.1074/jbc.M305101200Giaccia A, 2003, NAT REV DRUG DISCOV, V2, P803, DOI 10.1038/nrd1199Janssen HLA, 2003, J HEPATOL, V39, P414, DOI 10.1016/S0168-8278(03)00265-4Yeo EJ, 2003, J NATL CANCER I, V95, P516Welsh SJ, 2003, MOL CANCER THER, V2, P235Hirasawa K, 2003, CANCER RES, V63, P348Alain T, 2002, BLOOD, V100, P4146, DOI 10.1182/blood-2002-02-0503Ring CJA, 2002, J GEN VIROL, V83, P491, DOI 10.1099/vir.0.18098-0Russel FGM, 2002, ANNU REV PHYSIOL, V64, P563Clarke P, 2001, ONCOGENE, V20, P6910Jaakkola P, 2001, SCIENCE, V292, P468Chun YS, 2001, BIOCHEM PHARMACOL, V61, P947Hockel M, 2001, J NATL CANCER I, V93, P266Tanimoto K, 2000, EMBO J, V19, P4298Maxwell PH, 1999, NATURE, V399, P271Coffey MC, 1998, SCIENCE, V282, P1332Teng CM, 1997, EUR J PHARMACOL, V320, P161Levine AJ, 1997, CELL, V88, P323NIBERT ML, 1991, J VIROL, V65, P1960DILLER L, 1990, MOL CELL BIOL, V10, P5772ROSEN L, 1963, AM J HYG, V77, P29