期刊
MOLECULAR CANCER
卷 13, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1476-4598-13-217
关键词
Poly(I:C); Reactive oxygen species; Renal cell carcinoma; Caspase-2; 2-5A system
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [25430150, 24501331]
- Shimane University SUIGANN Project
- Grants-in-Aid for Scientific Research [24501331, 25430150] Funding Source: KAKEN
Background:Synthetic double-stranded RNA poly(I:C) is a useful immune adjuvant and exhibits direct antitumor effects against several types of cancers. In this study, we elucidated the mechanisms underlying the effects induced in poly(I:C)-transfected human renal cell carcinoma (RCC) cells. Results: In contrast to the lack of an effect of adding poly(I:C), poly(I:C) transfection drastically decreased RCC cell viability. Poly(I:C) transfection induced reactive oxygen species (ROS)-dependent apoptosis in RCC cells and decreased the mitochondrial membrane potential (Delta psi m). Treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, suppressed apoptosis and restored the Delta psi m. Although the levels of phosphorylated gamma H2A.X, an indicator of DNA damage, increased in poly(I:C)-transfected RCC cells, NAC treatment decreased their levels, suggesting ROS-mediated DNA damage. Furthermore, poly(I:C) transfection increased the levels of phosphorylated p53, NOXA, and tBid. Immunoblots and assays with a panel of caspase inhibitors revealed that poly(I:C) transfection-induced apoptosis was dependent on caspase-8 and -9, as well as caspase-2. Alternatively, poly(I:C) transfection increased mRNA expression of interferon (IFN)-beta, and treatment with IFN-beta suppressed growth of RCC cells without apoptosis. In addition, cyclinD1 and c-Myc expression decreased in poly(I:C)-transfected RCC cells. Moreover, RNA interference experiments revealed that poly(I:C) transfection exerted apoptotic effects on RCC cells through innate adjuvant receptors and the 2-5A system, the latter of which induces apoptosis in virus-infected cells. Conclusions:These results suggest that poly(I:C) transfection induced two types of effects against RCC cells such as apoptosis, as a result of ROS-mediated DNA damage, and IFN-beta-mediated growth arrest, both of which were exerted via innate adjuvant receptors and the 2-5A system.
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