title: Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ.
abstract: Src homology-2 domain-containing phosphatase (SHP) 2, an oncogenic phosphatase, inhibits type II immune interferon (IFN)-γ signaling by subverting signal transducers and activators of transcription 1 tyrosine phosphorylation and activation. For cancer immunoediting, this study aimed to investigate the decrease of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein, leading to cellular impairment of IFN-γ signaling. In comparison with human lung adenocarcinoma A549 cells, the natural PTEN loss in another human lung adenocarcinoma line, PC14PE6/AS2 cells, presents reduced responsiveness in IFN-γ-induced IFN regulatory factor 1 activation and CD54 expression. Artificially silencing PTEN expression in A549 cells also caused cells to be unresponsive to IFN-γ without affecting IFN-γ receptor expression. IFN-γ-induced inhibition of cell proliferation and cytotoxicity were demonstrated in A549 cells but were defective in PC14PE6/AS2 cells and in PTEN-deficient A549 cells. Aberrant activation of SHP2 by ROS was specifically shown in PC14PE6/AS2 cells and PTEN-deficient A549 cells. Inhibiting ROS and SHP2 rescued cellular responses to IFN-γ-induced cytotoxicity and inhibition of cell proliferation in PC14PE6/AS2 cells. These results demonstrate that a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-γ.
authors.affiliation: Translational Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Tzu-Hui
authors.initials: TH
authors.lastname: Chiang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Tseng
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. Electronic address: cflin2014@tmu.edu.tw.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019139:Tumor Escape
chemical_list: D017382:Reactive Oxygen Species; D007371:Interferon-gamma; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: IFN-γ; PTEN; ROS; SHP2; Signaling