Investigating the Involvement of Oncogenic Factors in Inducing Inhibition of Autophagy and IFN-γ Resistance

• Main Authors: Tzu-HuiChiang, 江姿慧
• Other Authors: Chiou-Feng Lin
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/4p8e7v

碩士 === 國立成功大學 === 臨床醫學研究所 === 102 === Nature killer and T cells produce interferon (IFN)-γ, perforin, granzymes, CD95 ligand, and tumor necrosis factor-related apoptosis-inducing ligand to retard tumor progression through cytotoxic induction. However, cancer cells may induce immunosuppression escape from immunosurveillance in the process of cancer immunoediting. Basically, IFN-γplays an important role in host immunosurveillance. Our previous findings showed that IFN-γ-induced autophagy facilitates IFN-γ signal transduction. In this study, we hypothesized that manipulating autophagy by oncogenic factors may cause IFN-γ resistance as a strategy for immune escape during tumorigenesis. IFN-γ activated Janus kinase/signal transducers and activator (JAK/STAT) signaling followed by an increase in autophagy in A549 human lung adenocarcinoma cells; however, either IFN-γ signaling or autophagy was defective in AS2 lung adenocarcinoma cells. As demonstrated in Atg5-deficient A549 cells, inhibition of autophagy resulted in IFN-γ resistance. Loss of autophagy increased reactive oxygen species (ROS)-activated Src homology domain containing phosphatase 2 (SHP2) activation that contributed to defect in IFN-γ signaling. In addition, IFN-γ induced STAT1 activation and autophagy independently of p53. Notably, excessive B-cell lymphoma 2 (Bcl-2) expression and mammalian target of rapamycin (mTOR) signaling determined cellular resistance to IFN-γ-induced autophagy as well as STAT1 activation. Moreover, decrease of phosphatase and tensin homolog (PTEN), the upstream of Bcl-2 and mTOR, also disrupted IFN-γ signaling that demonstrated in AS2 and PTEN-deficient A549 cells. Besides, PTEN decrease also caused increase ROS-activated SHP2. IFN-γ induced cytotoxicity effectively in A549 cells but not in AS2 cells. Inhibition of ROS and SHP2 reversed the effect of IFN-γ-induced cytotoxicity. Furthermore, overexpression of Bcl-2 and Akt which is the upstream of mTOR also interfered the IFN-γ signaling in the human embryonic kidney HEK293T cells. These findings indicate that oncogenic effects by aberrant PTEN expression and downstream signaling, Bcl-2 and mTOR, cause not only inhibition of autophagy but also IFN-γ resistance. These results provide evidence that oncogenic inhibition of autophagy may plays an essential role on tumorigenesis by interfering anticancer IFN-γ.