美國冷泉港實驗室（CSHL）研究人員在腫瘤細胞中發(fā)現(xiàn)3種阻抑蛋白，可影響丙酮酸激酶的兩個亞型的剪接，從而改變細胞代謝機制,。該發(fā)現(xiàn)有助于科學家理解并克服困擾醫(yī)學界長達80年的難題——“瓦伯格效應”，并將有助于找到一種抑制腫瘤細胞代謝和腫瘤生長的新方法,。相關研究成果刊發(fā)在最近的《美國國家科學院院刊》網(wǎng)絡版上,。
20世紀30年代，德國生物化學家奧托·瓦伯格發(fā)現(xiàn),，腫瘤和正常成體組織存在著代謝差異,，它們通過糖酵解產(chǎn)能,，并產(chǎn)生大量的副產(chǎn)品——乳酸。這種代謝性質(zhì)使得腫瘤細胞的耗糖速度遠大于正常細胞,。這種腫瘤細胞對糖酵解通路產(chǎn)能依賴增強的現(xiàn)象,，稱為“瓦伯格效應”，它會極快地促進細胞增生和腫瘤生長,。而最近有研究表明,，是一種叫做PK-M2（丙酮酸激酶M2）的蛋白促進了腫瘤細胞的這種代謝，對腫瘤的形成和生長起著至關重要的作用,。
PK-M2是丙酮酸激酶的一個亞型,，而其另一個亞型PK-M1，則與M2不同,，是無害的,。這兩種亞型都源于同一基因——PK-M基因。該基因以一種獨一無二的方式進行可變剪接（即基因的mRNA前體按不同的方式剪接,，產(chǎn)生出兩種或更多種mRNA）,，生成M1和M2兩種亞型。在腫瘤細胞中,，PK-M基因的可變剪接為何會只產(chǎn)生危險的M2,，而不產(chǎn)生無害的M1，則一直是個謎團,。
美國紐約冷泉港實驗室阿德里安·克萊內(nèi)爾教授領導的研究小組,，對多種類型癌癥細胞中的眾多剪接因子進行了篩查，最終發(fā)現(xiàn)了決定著M1和M2開關的3種剪接阻抑蛋白,。研究人員發(fā)現(xiàn),，這3種蛋白在腫瘤細胞中的含量很高，是它們抑制了M1亞型的剪接,，使腫瘤細胞只產(chǎn)出M2,。通過降低細胞中這3種蛋白的水平，可降低M2水平和乳酸生成量,，恢復M1的生成,，從而在很大程度上逆轉(zhuǎn)“瓦伯格效應”。
克萊內(nèi)爾指出,，這3種阻抑蛋白被阻斷后,，細胞并不會完全停止M2的生產(chǎn)，這表明可能還有其他的剪接因子影響著M1和M2的開關,。
目前該研究團隊正在尋找其他可能的剪接因子。而這種恢復正常的代謝狀態(tài)是否會阻礙腫瘤細胞的快速生長,，則有待進一步研究,。
克萊內(nèi)爾表示,，雖然對于“瓦伯格效應”還有幾個基本問題尚未解決,，目前也還不十分清楚該效應的作用機制，但關于細胞代謝機制的研究或可有助于揭開這一謎題,，從而發(fā)現(xiàn)新的分子藥物標靶,，開發(fā)出剪接因子抑制藥物和逆轉(zhuǎn)“瓦伯格效應”的藥物,，通過改變腫瘤細胞的代謝機制來治療癌癥。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS January 19, 2010, doi: 10.1073/pnas.0914845107
The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism
Cynthia V. Clowera,1, Deblina Chatterjeeb,c,1, Zhenxun Wangb,d, Lewis C. Cantleya, Matthew G. Vander Heidena,e,3, and Adrian R. Krainerb,c,d,2
aDivision of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
cGraduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794;
dWatson School of Biological Sciences, Cold Spring Harbor, NY 11724; and
eDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines—although some M1 mRNA is expressed in cell lines derived from brain tumors—and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.
