Cell:癌細胞逃避細胞凋亡的新機制被發現

生物谷報導：癌細胞通過提高酶GAPDH的水平，不僅能夠逃避主要自我破壞程序——凋亡，而且還會逃避後備的CICD程序。

St.  Jude（聖吉德兒童研究醫院）研究人員發現一些異常細胞通過增加能量水平和修復損傷而逃避凋亡的機制，對研究癌細胞生存和繁衍的關鍵策略提供了參考。研究人員認為某種能夠破壞癌細胞阻止後備程序能力的藥物有助於細胞凋亡，並且這種藥物比標準化療更有效，毒性更低。相關報導刊登於6月1日《Cell》雜誌。

    許多因素比如會使細胞癌化的基因突變都會激發凋亡。凋亡過程中，線粒體膜出現孔洞並洩漏激活caspases的細胞色素C，caspases進一步激活一系列細胞凋亡事件。文章高級作者、St.  Jude免疫科主任Douglas  Green博士說，膜產生小孔的過程——線粒體外膜滲透性（mitochondrial  outer  membrane  permeability，MOMP）——經常成為自殺的極限點。MOMP激發凋亡，但如果caspases缺失而導致凋亡失敗，後備的caspases 非依賴性細胞死亡（caspase-independent  cell  death  ，CICD）程序會接管過程。

    之前研究證實，MOMP釋放細胞色素C後，缺乏caspases等凋亡所需蛋白的細胞發生癌變。但如果CICD發揮活性，這種戰勝死亡的勝利是短暫的。然 而某些癌細胞不僅通過清除caspases活性躲避凋亡，而且會阻止CICD。Green說："我們研究的目的是弄清無caspases活性的癌細胞繞過 CICD的機制。"

    St.  Jude小組發現無caspases活性且不能凋亡的細胞，為了抵消CICD能力而提高酶GAPDH的水平。GAPDH支持線粒體，激活特定預防或修復細胞損傷的基因而防止CICD。研究結果還提示，GAPDH水平上升提高了自我吞噬作用（細胞"嚼碎"殘骸和被破壞的成分的過程）的能量。處理完受損線粒體後，細胞能夠更換這些致命成分。

    Green說，我們發現缺少caspases活性時，細胞在一周內能夠避免CICD發生，開始再次繁殖。這代表細胞恢復足夠線粒體，恢復正常細胞功能所需 的時間。GAPDH挽救細胞於CICD，提示阻斷這種酶有可能殺死缺少caspases活性且不能進行凋亡的異常細胞。這種策略將是新的抗癌藥物的基礎。

    St.  Jude的研究是在培養基中完成的。研究人員將正常細胞暴露於癌症藥物或其它激發凋亡的試劑，然後阻斷凋亡研究CICD。GAPDH反應似乎代表了基本的 再生事件。證實這種假說還需要進行在體研究，特別是尋找促進無caspases活性的癌細胞進行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

 

相關報導：

caspase家族及在細胞凋亡中的作用 

非caspase依賴的化療新手段 

《Cell》：凋亡中caspase影響了線粒體的呼吸 

《Cell》：caspase活化的機制 

Caspase對線粒體凋亡反應的激活 

凋亡過程中Caspase的級聯放大 

Caspase 信號級聯通路在細胞凋亡中的作用 

細胞凋亡中的Caspase家族