title: Oncotropic H-1 parvovirus infection degrades HIF-1α protein in human pancreatic cancer cells independently of VHL and RACK1.
abstract: Overexpression of HIF-1α, a transcription factor responsive to hypoxia, is frequently observed in malignant tumors, which sometimes show resistance to chemotherapy and radiation therapy. Consequently, decrease of HIF-1α through virotherapy offers a logical strategy for the treatment of aggressive tumors. In this study, we found that infection with the oncolytic H-1 parvovirus decreased HIF-1α protein levels in pancreatic cancer cells under CoCl2 or hypoxia. The H-1 virus-induced decrease of HIF-1α was regulated by a proteasome-mediated pathway. Suppression of VHL, an E3 ligase and a critical regulator of HIF-1α, or enforced expression of UCP, an E2 ubiquitin-conjugating enzyme, failed to inhibit the H-1 virus-induced decrease of HIF-1α. Furthermore, siRNA-mediated suppression of RACK1, another regulator of HIF-1α, did not prevent H-1 viral infection from lowering HIF-1α protein levels. Although decrease of HIF-1α was observed after H-1 viral infection, constitutive expression of HIF-1α limited H-1 viral replication. After combined treatment with H-1 parvovirus and YC-1, an inhibitor of HIF-1α, the apoptosis of pancreatic cancer cells was greater than after treatment with H-1 virus alone or YC-1 alone. Accordingly, we propose that H-1 parvovirus could be used with YC-1 as a potential therapeutic agent against aggressive tumors exhibiting hypoxia and increased levels of HIF-1α.
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Il-Rae
authors.initials: IR
authors.lastname: Cho
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Sirichat
authors.initials: S
authors.lastname: Kaowinn
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Moon
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Soh
authors.affiliation: Department of Microbiology, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Ho Young
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Gene Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
authors.forename: Cho-Rok
authors.initials: CR
authors.lastname: Jung
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea.
authors.forename: Hayne
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736, Republic of Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000378:metabolism; D052661:H-1 parvovirus; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010322:Parvoviridae Infections / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019204:GTP-Binding Proteins; C497446:VHL protein, human