title: HIF-1α downregulation and apoptosis in hypoxic prostate tumor cells infected with oncolytic mammalian orthoreovirus.
abstract: Hypoxia has emerged as one of the most important drivers of tumor aggression, metastasis, and poor clinical outcome in many cancers.In prostate cancer (PCa), hypoxia has been strongly correlated to biochemical failure and local recurrence. However, current PCa treatment options do not address hypoxic cells highlighting a critical gap in existing therapies and the need for development of therapies that target hypoxic prostate tumor cells. Mammalian orthoreovirus (MRV) is an oncolytic virus that targets tumor cells over normal cells which has been shown to be safe and effective against many cancers in vitro, in animal models, and in human clinical trials. We found that MRVinfects and replicates in hypoxic prostate tumor cells to levels comparable to normoxic cells leading to apoptosis and cell death. In addition, the regulatory subunit (HIF-1α) of the master transcriptional regulator of hypoxia, HIF-1, was significantly downregulated in infected cells. HIF-1α downregulation was found to occur via ubiquitin-dependent proteasome-mediated degradation and translational inhibition. Virus-mediated HIF-1α degradation required the HIF-1α PAS domain and expression of the receptor for activated kinase C (RACK1) protein. These data provide evidence that MRV may be a viable therapeutic option for targeting hypoxic cells and HIF-1α in PCa.
authors: Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA.
authors: Pooja
authors: P
authors: Gupta-Saraf
authors: Cathy L
authors: CL
authors: Miller
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000821:virology; D030102:Orthoreovirus, Mammalian; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D012088:Reoviridae Infections / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors