Cell：癌细胞两次逃避凋亡的机制
生物谷报道： St. Jude（圣吉德儿童研究医院）研究人员发现一些异常细胞通过增加能量水平和修复损伤而逃避凋亡的机制，对研究癌细胞生存和繁衍的关键策略提供了参考。研究人员认为某种能够破坏癌细胞阻止后备程序能力的药物有助于细胞凋亡，并且这种药物比标准化疗更有效，毒性更低。相关报道刊登于6月1日Cell 杂志。
癌细胞通过提高酶CAPDH的水平，不仅能够逃避主要自我破坏程序——凋亡，而且还会逃避后备的CICD程序。
许多因素会使细胞癌化的基因突变近而激发凋亡。凋亡过程中，线粒体膜出现孔洞并泄漏激活caspases的细胞色素C，caspases进一步激活一系列细胞凋亡事件。文章高级作者St. Jude免疫科主任Douglas Green博士说，膜产生小孔的过程——线粒体外膜渗透性（mitochondrial outer membrane permeability，MOMP）——经常成为自杀的极限点。MOMP激发凋亡，但如果caspases缺失而导致凋亡失败，后备的caspases非依赖性细胞死亡（caspase-independent cell death ，CICD）程序会接管过程。
之前研究证实，MOMP释放细胞色素C后，缺乏caspases等凋亡所需蛋白的细胞发生癌变。但如果CICD发挥活性，这种战胜死亡的胜利是短暂的。然而某些癌细胞不仅通过清除caspases活性躲避凋亡，而且会阻止CICD。Green说：“我们研究的目的是弄清无caspases活性的癌细胞绕过CICD的机制。”
St. Jude的研究是在培养基中完成的。研究人员将正常细胞暴露于癌症药物或其它激发凋亡的试剂，然后阻断凋亡研究CICD。GAPDH反应似乎代表了基本的再生事件。证实这种假说还需要进行在体研究，特别是寻找促进无caspases活性的癌细胞进行CICD的方法。
St. Jude小组发现无caspases活性且不能凋亡的细胞，为了抵消CICD能力而提高酶GAPDH的水平。GAPDH支持线粒体，激活特定预防或修复细胞损伤的基因而防止CICD。研究结果还提示，GAPDH水平上升提高了自我吞噬作用（细胞“嚼碎”残骸和被破坏的成分的过程）的能量。处理完受损线粒体后，细胞能够更换这些致命成分。
Green说，我们发现缺少caspases活性时，细胞在一周内能够避免CICD发生，开始再次繁殖。这代表细胞恢复足够线粒体，恢复正常细胞功能所需的时间。GAPDH挽救细胞于CICD，提示阻断这种酶有可能杀死缺少caspases活性且不能进行凋亡的异常细胞。这种策略将是新的抗癌药物的基础。
原始出处:
Cell, Vol 129, 983-997, 01 June 2007
Article
GAPDH and Autophagy Preserve Survival after Apoptotic Cytochrome c Release in the Absence of Caspase Activation
Anna Colell,1,8 Jean-Ehrland Ricci,2,8 Stephen Tait,3 Sandra Milasta,3 Ulrich Maurer,4 Lisa Bouchier-Hayes,3 Patrick Fitzgerald,3 Ana Guio-Carrion,5 Nigel J. Waterhouse,6 Cindy Wei Li,5 Bernard Mari,7 Pascal Barbry,7 Donald D. Newmeyer,5 Helen M. Beere,3 and Douglas R. Green3,
1 Department of Cell Death and Proliferation, Institut d'Investigacions Biomediques de Barcelona (IIBB-CSIC), IDIBAPS, 08036 Barcelona, Spain
2 Inserm, U526, Equipe Avenir, Universite de Nice Sophia-Antipolis, IFR 50, Faculte de Medecine, 28 Av de Valombrose, 06107 Nice, Cedex 02, France
3 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
4 Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
5 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA
6 Peter MacCallum Cancer Centre, and The Department of Pathology, University of Melbourne, Melbourne, Victoria 8006, Australia
7 CNRS, Université de Nice Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, F-06560 Sophia Antipolis, France
Corresponding author
Douglas R. Green
douglas.green@stjude.org
Abstract
In cells undergoing apoptosis, mitochondrial outer-membrane permeabilization (MOMP) is followed by caspase activation promoted by released cytochrome c. Although caspases mediate the apoptotic phenotype, caspase inhibition is generally not sufficient for survival following MOMP; instead cells undergo a “caspase-independent cell death” (CICD). Thus, MOMP may represent a point of commitment to cell death. Here, we identify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a critical regulator of CICD. GAPDH-expressing cells preserved their clonogenic potential following MOMP, provided that caspase activation was blocked. GAPDH-mediated protection of cells from CICD involved an elevation in glycolysis and a nuclear function that correlated with and was replaced by an increase in Atg12 expression. Consistent with this, protection from CICD reflected an increase in and a dependence upon autophagy, associated with a transient decrease in mitochondrial mass. Therefore, GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD.
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