Gupta-Saraf Pooja, Miller Cathy L
Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA.
Oncotarget. 2014 Jan 30;5(2):561-74. doi: 10.18632/oncotarget.1767.
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.
缺氧已成为许多癌症中肿瘤侵袭、转移和临床预后不良的最重要驱动因素之一。在前列腺癌（PCa）中，缺氧与生化失败和局部复发密切相关。然而，目前的PCa治疗方案并未针对缺氧细胞，这凸显了现有疗法中的关键差距，以及开发针对缺氧前列腺肿瘤细胞的疗法的必要性。哺乳动物正呼肠孤病毒（MRV）是一种溶瘤病毒，它靶向肿瘤细胞而非正常细胞，在体外、动物模型和人类临床试验中已被证明对许多癌症安全有效。我们发现MRV在缺氧前列腺肿瘤细胞中感染并复制至与常氧细胞相当的水平，导致细胞凋亡和死亡。此外，缺氧的主要转录调节因子HIF-1的调节亚基（HIF-1α）在感染细胞中显著下调。发现HIF-1α下调是通过泛素依赖性蛋白酶体介导的降解和翻译抑制发生的。病毒介导的HIF-1α降解需要HIF-1α PAS结构域和活化蛋白激酶C受体（RACK1）蛋白的表达。这些数据提供了证据，表明MRV可能是靶向PCa中缺氧细胞和HIF-1α的可行治疗选择。
