真菌次级代谢产物rasfonin促进肾癌细胞发生自噬、凋亡及程序性坏死
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- 论文作者：孙慧 ; 车永胜 ; 姜学军
- 年：2016
- 作者机构：中国科学院微生物研究所真菌学国家重点实验室;中国人民解放军军事医学科学院毒物药物研究所;
- 论文关键词：rasfonin ; EGFR/MAPK ; 细胞自噬 ; 程序性细胞死亡 ; RIP-1
- 会议召开时间：2016-08-19
- 会议录名称：中国菌物学会2016年学术年会论文摘要集
- 英文会议录名称：Abstracts of 2016 Mycological Society of China Annual Meeting
- 语种：中文
- 分类号：R737.11
- 学会代码：ZGVL
- 会议名称：中国菌物学会2016年学术年会
- 会议地点：中国福建福州
- 主办单位：中国菌物学会
- 学会名称：中国菌物学会
- 页数：3
- 文件大小：703k
- 原文格式：D
- 会议级别：全国
摘要
Rasfonin是一种α-吡喃酮类的真菌次级代谢产物,最初发现其能抑制小G蛋白ras而得名。车永胜教授课题组从青藏高原海拔4千多米的土壤样品中分离到真菌Doratomyces sp.,该菌的发现使获取rasfonin的效率大大提高。在之前的研究中,我们发现rasfonin能够诱导肾癌细胞自噬和凋亡的发生,然而其对另一种细胞死亡方式——程序性坏死的影响却未见报道,且rasfonin引起的三种程序性细胞死亡方式间的关系也不清楚。通过研究我们发现rasfonin能抑制多种肿瘤细胞的增殖,而程序性坏死的抑制剂necrostatin-1(Nec-1)能减少rasfonin引起的细胞活性丢失;流式细胞结果表明Nec-1能抑制rasfonin引起细胞凋亡和坏死,说明该化合物能促进细胞的程序性坏死。通过透射电镜,我们观察到rasfonin能迅速引起细胞囊泡结构的增加,而处理至12 h后,细胞会出现明显的坏死样形态特征。免疫印迹检测结果表明rasfonin能促进自噬标记蛋白微管相关蛋白1轻链3(LC3)II的积累,同时伴有凋亡底物PARP-1切割的增加。Nec-1对rasfonin诱导的细胞自噬具有双向调节作用,敲降程序性坏死关键蛋白RIP1增加了rasfonin引起的细胞凋亡。另外我们发现,rasfonin能上调EGFR的磷酸化,激活MAPK信号通路;抑制EGFR/MAPK信号通路对该化合物引起的自噬、凋亡、程序性坏死均有影响。综上,rasfonin能够引起多种程序性细胞死亡,且不同死亡方式间存在着转换。
引文
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Tomikawa T,Shin-Ya K,Furihata K,Kinoshita T,Miyajima A,Seto H,Hayakawa Y.2000.Rasfonin,a new apoptosis inducer in ras-dependent cells from Talaromyces sp.J Antibiot(Tokyo)53(8):848-50.
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Zhang N,Chen Y,Jiang R,Li E,Chen X,Xi Z,Guo Y,Liu X,Zhou Y,Che Y et al..2011.PARP and RIP 1 arerequired for autophagy induced by 11'-deoxyverticillin A,which precedes caspase-dependent apoptosis.Autophagy 7(6):598-612.
Andrabi SA,Kim NS,Yu S-W,Wang H,Koh DW,Sasaki M,Klaus JA,Otsuka T,Zhang Z,Koehler RC et al..2006.Poly(ADP-ribose)(PAR)polymer is a death signal.Proceedings of the National Academy of Sciences of the United States of America 103(48):18308-18313.
Berardi DE,Campodonico PB,Diaz Bessone MI,Urtreger AJ,Todaro LB.2011.Autophagy:friend or foe in breast cancer development,progression,and treatment.Int J Breast Cancer 2011:595092.
Cho YS.2014.Perspectives on the therapeutic modulation of an alternative cell death,programmed necrosis(review).Int J Mol Med 33(6):1401-6.
Degterev A,Hitomi J,Germscheid M,Ch'en IL,Korkina O,Teng X,Abbott D,Cuny GD,Yuan C,Wagner G et al..2008.Identification of RIP1 kinase as a specific cellular target of necrostatins.Nat Chem Biol4(5):313-321.
Edinger AL,Thompson CB.2004.Death by design:apoptosis,necrosis and autophagy.Current Opinion in Cell Biology 16(6):663-669.
Galluzzi L,Kepp O,Kroemer G.2009.RIP Kinases Initiate Programmed Necrosis.Journal of Molecular Cell Biology 1(1):8-10.
Gong J,Kumar SA,Graham G,Kumar AP.2014.FLIP:molecular switch between apoptosis and necroptosis.Mol Carcinog 53(9):675-85.
Grumati P,Coletto L,Sabatelli P,Cescon M,Angelin A,Bertaggia E,Blaauw B,Urciuolo A,Tiepolo T,Merlini Let al..2010.Autophagy is defective in collagen VI muscular dystrophies,and its reactivation rescues myofiber degeneration.Nat Med 16(11):1313-1320.
Han W,Xie J,Fang Y,Wang Z,Pan H.2012.Nec-1 Enhances Shikonin-Induced Apoptosis in Leukemia Cells by Inhibition of RIP-1 and ERK1/2.International Journal of Molecular Sciences 13(6):7212-7225.
Hanahan D,Weinberg RA.2011.Hallmarks of Cancer:The Next Generation.Cell 144(5):646-674.
Hilgeroth A.2002.Dimeric 4-Aryl-1,4-dihydropyridines:development of a third class of nonpeptidic HIV-1protease inhibitors.Mini Rev Med Chem 2(3):235-45.
Holler N,Zaru R,Micheau O,Thome M,Attinger A,Valitutti S,Bodmer J-L,Schneider P,Seed B,Tschopp J.2000a.Fas triggers an alternative,caspase-8-independent cell death pathway using the kinase RIP as effector molecule.Nat Immunol 1(6):489-495.
Holler N,Zaru R,Micheau O,Thome M,Attinger A,Valitutti S,Bodmer JL,Schneider P,Seed B,Tschopp J.2000b.Fas triggers an alternative,caspase-8-independent cell death pathway using the kinase RIP as effector molecule.Nat Immunol 1(6):489-95.
Kabeya Y,Mizushima N,Yamamoto A,Oshitani-Okamoto S,Ohsumi Y,Yoshimori T.2004.LC3,GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation.Journal of Cell Science117(13):2805-2812.
Klionsky DJ,Abdalla FC,Abeliovich H,Abraham RT,Acevedo-Arozena A,Adeli K,Agholme L,Agnello M,Agostinis P,Aguirre-Ghiso JA et al..2012.Guidelines for the use and interpretation of assays for monitoring autophagy.Autophagy 8(4):445-544.
Klionsky DJ,Abdelmohsen K,Abe A,Abedin MJ,Abeliovich H,Acevedo Arozena A,Adachi H,Adams CM,Adams PD,Adeli K et al..2016.Guidelines for the use and interpretation of assays for monitoring autophagy(3rd edition).Autophagy 12(1):1-222.
Kovacs AL,Seglen PO.1982.Inhibition of hepatocytic protein degradation by inducers of autophagosome accumulation.Acta Biol Med Ger 41(1):125-30.
Kroemer G,Levine B.2008.Autophagic cell death:the story of a misnomer.Nature reviews.Molecular cell biology 9(12):1004-1010.
Kume S,Koya D.2015.Autophagy:A Novel Therapeutic Target for Diabetic Nephropathy.Diabetes&Metabolism Journal 39(6):451-460.
Levine B,Yuan J.2005.Autophagy in cell death:an innocent convict?The Journal of Clinical Investigation115(10):2679-2688.
Maiuri MC,Zalckvar E,Kimchi A,Kroemer G.2007.Self-eating and self-killing:crosstalk between autophagy and apoptosis.Nat Rev Mol Cell Biol 8(9):741-752.
Marrison LR,Dickinson JM,Fairlamb IJS.2002.Bioactive 4-substituted-6-methyl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines.Bioorganic&Medicinal Chemistry Letters12(24):3509-3513.
Mc Glacken GP,Fairlamb IJ.2005.2-Pyrone natural products and mimetics:isolation,characterisation and biological activity.Nat Prod Rep 22(3):369-85.
Mihaylova MM,Shaw RJ.2011.The AMP-activated protein kinase(AMPK)signaling pathway coordinates cell growth,autophagy,&metabolism.Nature cell biology 13(9):1016-1023.
Sun Y,Peng ZL.2009.Programmed cell death and cancer.Postgraduate Medical Journal 85(1001):134-140.
Tomikawa T,Shin-Ya K,Furihata K,Kinoshita T,Miyajima A,Seto H,Hayakawa Y.2000.Rasfonin,a new apoptosis inducer in ras-dependent cells from Talaromyces sp.J Antibiot(Tokyo)53(8):848-50.
Xiao Z,Li L,Li Y,Zhou W,Cheng J,Liu F,Zheng P,Zhang Y,Che Y.2014.Rasfonin,a novel 2-pyrone derivative,induces ras-mutated Panc-1 pancreatic tumor cell death in nude mice.Cell Death Dis 5(5):e1241-.
Yang Z,Klionsky DJ.2010.Eaten alive:a history of macroautophagy.Nature cell biology 12(9):814-822.
Zhang N,Chen Y,Jiang R,Li E,Chen X,Xi Z,Guo Y,Liu X,Zhou Y,Che Y et al..2011.PARP and RIP 1 arerequired for autophagy induced by 11'-deoxyverticillin A,which precedes caspase-dependent apoptosis.Autophagy 7(6):598-612.