The Role Of PI3K/AKT Signaling In The Differential Death Of Hepatocarcinoma Cells Induced By Newcastle Disease Virus

Newcastle Disease Virus(NDV) is a type strain of avian paramyxoviruses, which can selectively replicate in cancer cells and induce oncolysis. Clinical trials demonstrated NDV less harmful to humans. There are only a few reports show that human infected with Newcastle disease virus have mild symptoms such as lymphadenitis and conjunctivitis, but soon recovered. In addition to direct killing tumor virus, NDV infection can affect the immunogenicity of the tumor cells or induce an immune response in order to achieve the effect of killing tumor cells. Now,NDV-based oncolytic therapy has become a hot area of current cancer therapy.Primary liver cancer is the third most common cancer and about 11 million people died from liver cancer each year in China. The early diagnosis of primary liver cancer is difficult. Surgery is the main treatment with adjuvant therapy including chemotherapy and radiation therapy. The effects of these treatments received are not ideal, so it should break the traditional thinking to find new therapies. Oncolytic viral therapies are new cancer therapeutic approaches for cancer patients with great potential and less side effects. The the disadvantage of this therapy is that cancer cells will be tolerated to virus during the treatment process. So we need to investigate how to improve the effienacy of oncolytic therapy in the future.In the present study, we observed different activity of AKT kinase in two kinds of HCC cell lines after infection with NDV virus. Treatment with AKT kinase specific inhibitor significantly decrease AKT activity and changes NDV sensitive Huh7 cells to a resistant one. In contrast, NDV replication increased and higher oncolytic efficiency was observed in NDV resistant HCC621 cells treatment with AKT kinase activator Fumonisin B1. We found a increase of NDV virus which dependent on the infection time during the analysis of NDV-induced oncolysis in licer cancer cells.In early infection time pionts, the NDV-indcued IFN-? conversely inhibits NDV replication, resulting in decreased viral replication efficiency in cancer cells.We also found an inverse correlation between the AKT kinase activity and the sensitivity of cancer cells to NDV virus. Further study indicated that the intracellular NDV virus induce different level of IFN-?dependent on AKT kinase activity. The apoptosis pathway was involved in NDV-induced oncolysis.By studying NDV virus-induced apoptotic sianaling pathway, we can have a better understanding of the mechanisms that cancer cells resistant to NDV.