Oncotropic H-1 parvovirus infection degrades HIF-1α protein in human pancreatic cancer cells independently of VHL and RACK1

Cho,Il-Rae; Kaowinn,Sirichat; Moon,Jeong; Soh,Jiwon; Kang,Ho Young; Jung,Cho-Rok; Oh,Sangtaek; Song,Hayne; Koh,Sang Seok; Chung,Young-Hwa

doi:10.3892/ijo.2015.2922

Oncotropic H-1 parvovirus infection degrades HIF-1α protein in human pancreatic cancer cells independently of VHL and RACK1

Authors:
- Il-Rae Cho
- Sirichat Kaowinn
- Jeong Moon
- Jiwon Soh
- Ho Young Kang
- Cho-Rok Jung
- Sangtaek Oh
- Hayne Song
- Sang Seok Koh
- Young-Hwa Chung
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Affiliations: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736, Republic of Korea, Department of Microbiology, Pusan National University, Busan 609-736, Republic of Korea, Gene Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea, Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea, Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea
Published online on: March 9, 2015 https://doi.org/10.3892/ijo.2015.2922
Pages: 2076-2082

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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.

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