Title

丙型干擾素誘導肺上皮惡性腫瘤進行一種類胞外捕捉性死亡

Translated Titles

IFN-gamma induces a mimic extracellular trap cell death in lung epithelial maligancy

DOI

10.6844/NCKU.2013.00120

Authors

錢舜益

Key Words

丙型干擾素 ; 細胞自噬作用 ; 組蛋白瓜胺酸化 ; 胞外捕捉性死亡 ; 肺癌 ; IFN-γ ; autophagy ; hitone H3 citrullination ; ETosis ; lung cancer

PublicationName

成功大學微生物及免疫學研究所學位論文

Volume or Term/Year and Month of Publication

2013年

Academic Degree Category

碩士

Advisor

林秋烽

Content Language

英文

Chinese Abstract

丙型干擾素藉由細胞自噬作用來促進其訊息傳遞和生物功能包括發炎、抑菌以及抗癌。本篇研究著重探討細胞自噬作用對於丙型干擾素誘導細胞毒性的角色。丙型干擾素會造成肺癌細胞株A549生長抑制並產生細胞毒性。丙型干擾素不會造成細胞週期停滯卻誘導細胞凋亡的現象包括染色體的凝聚和磷脂醯絲胺酸胞外暴露,同時伴隨著細胞毒性相關的類細胞壞死現象。藉由細胞核的染色、體外核小體的偵測、電子顯微鏡觀察以及核纖層蛋白染色顯示丙型干擾素誘導類胞外捕捉性死亡,且這樣的現象是由caspase蛋白所調控。研究證實IRGM1以及ATF6蛋白調控細胞自噬作用進而促進丙型干擾素誘導細胞毒性、caspase-3蛋白的活化以及類胞外捕捉性死亡現象。由丙型干擾素誘導的NADPH氧化酶表現及下游活性氧化物會促使染色體損害進而促進類胞外捕捉性死亡。處理丙型干擾素會使得FADD蛋白會和細胞自噬體結合,顯示細胞自噬作用會誘導FADD蛋白調控caspase-3活化。在細胞自噬作用和caspase活化之後,丙型干擾素導致染色體損害並伴隨著ATR/ATM蛋白調控的類胞外捕捉性死亡以及細胞毒性產生。另外,丙型干擾素誘導的胞外捕捉性死亡取決於PAD4蛋白調控的組蛋白瓜胺酸化,而調控PAD4蛋白活化的機制包括染色體損害相關的ATR/ATM及NADPH氧化酶與內質網壓力相關的ATF6及鈣離子訊號。重要的是,生長抑制、細胞毒性、caspase-3蛋白活化、染色體損害以及類胞外捕捉性死亡在細胞自噬作用缺乏和具丙型干擾素抗性的肺癌細胞株PC14PE6/AS2無法產生。這些結果證實細胞自噬作用存在下,丙型干擾素誘導caspase調控的染色體損害伴隨著PAD4調控組蛋白瓜胺酸化的胞外捕捉性死亡現象,並提供新穎的丙型干擾素細胞毒性證據。

English Abstract

Interferon (IFN)-γ causes autophagy to facilitate signaling and bioactivities, including inflammation, anti-microbe, and anticancer. This study aims to investigate the role of autophagy in cytotoxicity of IFN-γ. IFN-γ induces growth inhibition and cytotoxicity in A549 human lung cancer cells. Without cell cycle arrest, the presence of apoptotic events, such as DNA condensation/fragmentation and phosphatidylserine externalization, accompanied by necrosis-like cell death was related to IFN-γ cytotoxicity. Surprisingly, nuclear staining, extracellular nucleosome detection, electronic microscopic observation, and lamin staining showed a mimic extracellular trap cell death (ETosis) caused by IFN-γ and regulated by caspases. Autophagy regulated by immunity-related GTPase family M protein (IRGM) 1 and activating transcription factor (ATF) 6 facilitated IFN-γ-induced cytotoxicity, caspase activation, and ETosis. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase-associated reactive oxygen species (ROS) generation also promoted Fas-associated protein with death domain (FADD) was co-localized with microtubule-associated protein 1 light chian (LC) 3 punctas under IFN-γ treatment, indicating that autophagy activates FADD-mediated caspase activation. Following autophagy and caspase activation, IFN-γ resulted in DNA damage followed by ataxia telangiectasia and Rad3-related protein (ATR)/ataxia-telangiectasia mutated (ATM)- and NADPH oxidase-regulated ETosis and cytotoxicity independent of p53. Moreover, IFN-γ-induced ETosis was depended on peptidyl arginine deiminase (PAD) 4-mediated histone 3 citrullination while the regulation of PAD4 was regulated by DNA damage-associated ATR/ATM and NADPH oxidase and endoplasmic reticulum stress-associated ATF6 and calcium signaling. Notably, growth inhibition, cytotoxicity, caspase-3 activation, DNA damage, and ETosis were defect in PC14PE6/AS2 human lung cancer cells while the cells showed autophagy insusceptibility as well as IFN-γ resistance. These results provide the novel evidence to demonstrate that, under autophagy, IFN-γ triggers caspase-mediated DNA damage-associated a mimic ETosis accompanied by PAD4-mediated H3 citrullination for cytotoxicity.

Topic Category 醫藥衛生 > 基礎醫學
醫學院 > 微生物及免疫學研究所
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Times Cited
  1. 郭明倫(2011)。壓電式扭力感測器之研製。中原大學機械工程研究所學位論文。2011。1-67。