生物谷報(bào)道：癌細(xì)胞通過(guò)提高酶GAPDH的水平，不僅能夠逃避主要自我破壞程序——凋亡,，而且還會(huì)逃避后備的CICD程序。
St. Jude（圣吉德兒童研究醫(yī)院）研究人員發(fā)現(xiàn)一些異常細(xì)胞通過(guò)增加能量水平和修復(fù)損傷而逃避凋亡的機(jī)制，對(duì)研究癌細(xì)胞生存和繁衍的關(guān)鍵策略提供了參考,。研究人員認(rèn)為某種能夠破壞癌細(xì)胞阻止后備程序能力的藥物有助于細(xì)胞凋亡，并且這種藥物比標(biāo)準(zhǔn)化療更有效,，毒性更低,。相關(guān)報(bào)道刊登于6月1日《Cell》雜志。
許多因素比如會(huì)使細(xì)胞癌化的基因突變都會(huì)激發(fā)凋亡,。凋亡過(guò)程中,，線粒體膜出現(xiàn)孔洞并泄漏激活caspases的細(xì)胞色素C，caspases進(jìn)一步激活一系列細(xì)胞凋亡事件,。文章高級(jí)作者,、St. Jude免疫科主任Douglas Green博士說(shuō)，膜產(chǎn)生小孔的過(guò)程——線粒體外膜滲透性（mitochondrial outer membrane permeability，MOMP）——經(jīng)常成為自殺的極限點(diǎn),。MOMP激發(fā)凋亡,，但如果caspases缺失而導(dǎo)致凋亡失敗，后備的caspases 非依賴性細(xì)胞死亡（caspase-independent cell death ,，CICD）程序會(huì)接管過(guò)程,。
之前研究證實(shí)，MOMP釋放細(xì)胞色素C后,，缺乏caspases等凋亡所需蛋白的細(xì)胞發(fā)生癌變,。但如果CICD發(fā)揮活性，這種戰(zhàn)勝死亡的勝利是短暫的,。然 而某些癌細(xì)胞不僅通過(guò)清除caspases活性躲避凋亡,，而且會(huì)阻止CICD。Green說(shuō)："我們研究的目的是弄清無(wú)caspases活性的癌細(xì)胞繞過(guò) CICD的機(jī)制,。"
St. Jude小組發(fā)現(xiàn)無(wú)caspases活性且不能凋亡的細(xì)胞,，為了抵消CICD能力而提高酶GAPDH的水平。GAPDH支持線粒體,，激活特定預(yù)防或修復(fù)細(xì)胞損傷的基因而防止CICD,。研究結(jié)果還提示，GAPDH水平上升提高了自我吞噬作用（細(xì)胞"嚼碎"殘骸和被破壞的成分的過(guò)程）的能量,。處理完受損線粒體后,，細(xì)胞能夠更換這些致命成分。
Green說(shuō),，我們發(fā)現(xiàn)缺少caspases活性時(shí),，細(xì)胞在一周內(nèi)能夠避免CICD發(fā)生，開(kāi)始再次繁殖,。這代表細(xì)胞恢復(fù)足夠線粒體,，恢復(fù)正常細(xì)胞功能所需 的時(shí)間。GAPDH挽救細(xì)胞于CICD,，提示阻斷這種酶有可能殺死缺少caspases活性且不能進(jìn)行凋亡的異常細(xì)胞,。這種策略將是新的抗癌藥物的基礎(chǔ)。
St. Jude的研究是在培養(yǎng)基中完成的,。研究人員將正常細(xì)胞暴露于癌癥藥物或其它激發(fā)凋亡的試劑,，然后阻斷凋亡研究CICD。GAPDH反應(yīng)似乎代表了基本的 再生事件,。證實(shí)這種假說(shuō)還需要進(jìn)行在體研究,，特別是尋找促進(jìn)無(wú)caspases活性的癌細(xì)胞進(jìn)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.
原文出處：
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]
作者簡(jiǎn)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
