Ch'ng Wei-Choong, Abd-Aziz Noraini, Ong Meng-Hua, Stanbridge Eric J, Shafee Norazizah
Department of Microbiology, Faculty of Biotechnology & Biomolecular Sciences, and Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia.
Cell Oncol (Dordr). 2015 Aug;38(4):279-88. doi: 10.1007/s13402-015-0229-5. Epub 2015 May 1.
Newcastle disease virus (NDV) is an oncolytic virus that is known to have a higher preference to cancer cells than to normal cells. It has been proposed that this higher preference may be due to defects in the interferon (IFN) responses of cancer cells. The exact mechanism underlying this process, however, remains to be resolved. In the present study, we examined the antiviral response towards NDV infection of clear cell renal cell carcinoma (ccRCC) cells. ccRCC is associated with mutations of the von Hippel-Lindau tumor suppressor gene VHL, whose protein product is important for eliciting cellular responses to changes in oxygen levels. The most common first line treatment strategy of ccRCC includes IFN. Unfortunately, most ccRCC cases are diagnosed at a late stage and often are resistant to IFN-based therapies. Alternative treatment approaches, including virotherapy using oncolytic viruses, are currently being investigated. The present study was designed to investigate the mechanistic pathways underlying the response of ccRCC cells to oncolytic NDV infection.
We found that NDV induces activation of NF-κB in ccRCC cells by inducing phosphorylation and subsequent degradation of IκBα. IκBα was found to be phosphorylated as early as 1 hour post-infection and to result in rapid NF-κB nuclear translocation and activation. Importantly, p38 MAPK phosphorylation was found to occur upstream of the NDV-induced NF-κB activation. Restoration of VHL in ccRCC cells did not result in a reduction of this phosphorylation. A similar phenomenon was also observed in several other cancer-derived cell lines.
Our data provide evidence for involvement of the p38 MAPK/NF-κB/IκBα pathway in NDV infection and subsequent induction of apoptosis in ccRCC cells.
新城疫病毒（NDV）是一种溶瘤病毒，已知其对癌细胞的偏好高于正常细胞。有人提出，这种更高的偏好可能是由于癌细胞的干扰素（IFN）反应存在缺陷。然而，这一过程的具体机制仍有待解决。在本研究中，我们检测了透明细胞肾细胞癌（ccRCC）细胞对NDV感染的抗病毒反应。ccRCC与冯·希佩尔-林道肿瘤抑制基因VHL的突变有关，其蛋白质产物对于引发细胞对氧水平变化的反应很重要。ccRCC最常见的一线治疗策略包括使用干扰素。不幸的是，大多数ccRCC病例在晚期才被诊断出来，并且通常对基于干扰素的治疗有抗性。目前正在研究包括使用溶瘤病毒进行病毒疗法在内的替代治疗方法。本研究旨在探讨ccRCC细胞对溶瘤NDV感染反应的机制途径。
我们发现NDV通过诱导IκBα的磷酸化和随后的降解来诱导ccRCC细胞中NF-κB的激活。发现IκBα在感染后1小时就被磷酸化，并导致NF-κB迅速核转位和激活。重要的是，发现p38 MAPK磷酸化发生在NDV诱导的NF-κB激活的上游。在ccRCC细胞中恢复VHL并没有导致这种磷酸化的减少。在其他几种癌症来源的细胞系中也观察到了类似的现象。
我们的数据为p38 MAPK/NF-κB/IκBα途径参与NDV感染以及随后诱导ccRCC细胞凋亡提供了证据。
