生物谷报道：癌细胞通过提高酶GAPDH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。
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。
许多因素比如会使细胞癌化的基因突变都会激发凋亡。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。
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。
Figure 1. GAPDH Protects Cells from Caspase-Independent Cell Death but Not from Apoptosis
(A) HeLa cells transduced with a virus encoding GAPDH were treated as indicated in the presence or in the absence of qVD-oph. Percent of viability was measured by propidium iodide staining and flow cytometry analysis.
(B) HeLa cells transduced with a control retrovirus or with a virus encoding GAPDH were treated with 1 μM staurosporine (STS) in the presence of 20 μM qVD-oph. After the indicated times GAPDH expression was assessed by Western blot.
(C) Same as in (B) in the presence or absence of qVD-oph. *p < 0.01 versus vector with qVD-oph.
(D) HeLa cells (transduced with control or GAPDH encoding retrovirus) were treated for 6 hr with Act D, etoposide, or STS as indicated ± the caspase inhibitor qVD-oph (20 μM). The caspase inhibitor was added 30 min before the apoptotic agents and replaced periodically at 24 hr intervals for 3 days. Colonies were stained with methylene blue and assessed 12 days after treatment.
(E) Treatment as in (D). Quantitation of the number of colonies under each condition 12 days after treatment.
(F) Cells (1 × 104/well) were treated for 6 hr as indicated in the presence of qVD-oph (20 μM). Viable cells were counted by trypan blue exclusion at the indicated times (up to 12 days). All results in the figure represent mean ± SD of three to five independent experiments.
原文出处：
Cell June 1, 2007: 129 (5)
GAPDH and Autophagy Preserve Survival after Apoptotic Cytochrome c Release in the Absence of Caspase Activationp983
Anna Colell, Jean-Ehrland Ricci, Stephen Tait, Sandra Milasta, Ulrich Maurer, Lisa Bouchier-Hayes, Patrick Fitzgerald, Ana Guio-Carrion, Nigel J. Waterhouse, Cindy Wei Li, Bernard Mari, Pascal Barbry, Donald D. Newmeyer, Helen M. Beere, and Douglas R. Green
[Summary] [Full Text] [PDF] [Supplemental Data]
作者简介：
Douglas R. Green, PhD
Member, St. Jude Faculty
Chair, Immunology
Peter C. Doherty Endowed Chair of Immunology
Departments
Immunology
Contact Information
Douglas R. Green, PhD
Chair, Department of Immunology
St. Jude Children’s Research Hospital
Education
PhD - Yale University, New Haven, Connecticut (1981)
Research Interests
Central mechanisms of apoptosis in cancer and the immune system
Selected Publications
Green DR. Apoptosis. In: Cells, edited by Lewin B, Cassimeris L, Lingappa VR, and Plopper G, Jones and Barlett Pub, Sudbury, pp 533-559, 2006.
Green DR, Chipuk JE. p53 and metabolish: Inside the TIGAR. Cell 126, 30-32, 2006.
Spierings DC, Lemmens EE, Grewal K, Schoenberger SP, Green DR. Duration of CTL activation regulates IL-2 production required for autonomous clonal expansion. Eur J Immunol 36;1707-1717, 2006.
Muñoz-Pinedo C, Guío-Carrión A, Goldstein JC, Fitzgerald P, Newmeyer DD, Green DR. Different mitochondrial inter-membrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. Proc Natl Acad Sci USA 103;11573-11578, 2006.
Chipuk JE, Bouchier-Hayes L, Green DR. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13;1396-1402, 2006.
Green DR. At the gates of death. Cancer Cell 9;328-330, 2006.
Chipuk JE, Green DR. Dissecting p53-dependent apoptosis. Cell Death Differ 13;994-1002, 2006.
Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of Mcl-1. Mol Cell 21;749-760, 2006.
Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Ulevitch RJ, Green DR, Nicholson DW. (shared senior authorship) Enhanced bacterial clearance and sepsis resistance in caspase-12 deficient mice. Nature 440;1064-1068, 2006.
Tu S, McStay GP, Boucher LM, Mak T, Beere HM, Green DR. In situ “trapping” of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nature Cell Biol 8;72-77, 2006.
Kiessling S, Green DR. Cell survival and proliferation in Drosophila S2 cells following apoptotic stress in the absence of the APAF-1 homology, ARK, or downstream caspases. Apoptosis 11;497-507, 2006.
Pagliari LJ, Kuwana T, Bonzon C, Tu S, Beere HM, Green DR. The multidomain pro-apoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 102;17975-17980, 2005.
Spierings D, McStay G, Saleh M, Bender C, Chipuk J, Maurer U, Green DR. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science 310;66-67, 2005.
Green DR, Kroemer G. Pharmacologic manipulation of cell death: clinical applications in sight? J Clin Invest 115;2610-2617, 2005.
Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR. Puma couples the nuclear and cytoplasmic pro-apoptotic function of p53. Science 309;1732-1735, 2005.
Green DR. Apoptotic pathways: ten minutes to dead. Cell 121;671-674, 2005.
Last update: February 2007
