HIF-1α downregulation and apoptosis in hypoxic prostate tumor cells infected with oncolytic mammalian orthoreovirus.
HIF-1α downregulation and apoptosis in hypoxic prostate tumor cells infected with oncolytic mammalian orthoreovirus.
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DOI：
10.18632/oncotarget.1767
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发表时间：
2014-01-30
期刊：
影响因子：
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通讯作者：
Miller CL
中科院分区：
文献类型：
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作者：
Gupta-Saraf P;Miller CL
缺氧已成为许多癌症中肿瘤侵袭、转移和不良临床结局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治疗方案没有解决低氧细胞，这突出了现有疗法中的关键差距，以及开发靶向低氧前列腺肿瘤细胞的疗法的需求。哺乳动物正呼肠孤病毒（MRV）是一种靶向肿瘤细胞而非正常细胞的溶瘤病毒，其已在体外、动物模型和人类临床试验中显示出对许多癌症安全有效。我们发现MRV在缺氧的前列腺肿瘤细胞中感染并复制到与常氧细胞相当的水平，导致细胞凋亡和细胞死亡。此外，缺氧的主要转录调节因子HIF-1的调节亚基（HIF-1a）在感染细胞中显著下调。HIF-1a下调通过泛素依赖性蛋白酶体介导的降解和翻译抑制而发生。病毒介导的HIF-1a降解需要HIF-1a PAS结构域和活化激酶C受体（RACK 1）蛋白的表达。这些数据提供了MRV可能是靶向PCa中的缺氧细胞和HIF-Ia的可行治疗选择的证据。
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 MRV infects 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-1a) of the master transcriptional regulator of hypoxia, HIF-1, was significantly downregulated in infected cells. HIF-1a downregulation was found to occur via ubiquitin-dependent proteasome-mediated degradation and translational inhibition. Virus-mediated HIF-1a degradation required the HIF-1a 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-la in PCa.