Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma.
Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma.
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DOI：
10.1371/journal.pone.0057610
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Pieper RO
中科院分区：
文献类型：
--
作者：
Mukherjee J;Phillips JJ;Zheng S;Wiencke J;Ronen SM;Pieper RO
正常组织表达M1异构体的丙酮酸激酶(PK)，它有助于产生丙酮酸并将其输送到线粒体中，以产生ATP。相比之下，肿瘤表达活性较低的PKM2亚型，它限制了丙酮酸的产生，并节省了糖酵解中间体来产生增殖所需的大分子。虽然高PKM2表达和低PK活性被认为是肿瘤的特征，但人们对PKM表达和PK活性如何在从低级别到高级别肿瘤的连续体中变化，以及这些变化与肿瘤生长的关系知之甚少。为了解决这个问题，我们测量了正常脑、神经前体细胞以及从良性I级毛细胞性星形细胞瘤到高度侵袭性IV级多形性胶质母细胞瘤(GBM)的一系列星形细胞瘤中PKM亚型的表达和PK活性。与正常脑组织相比，所有胶质瘤的PKM1表达和PK活性均降低。相反，尽管I-III级胶质瘤的PKM2RNA和蛋白表达水平都比正常脑略有增加，但无论是新生的还是从较低级别的肿瘤发展而来的GBM，PKM2RNA和蛋白的表达都进一步增加了3-5倍。低水平的PKM1表达和PK活性对细胞生长是重要的，因为PKM1的过度表达和伴随的PK活性的增加减缓了GBM细胞的生长。然而，PKM2表达的增加也很重要，因为shRNA介导的PKM2基因敲除降低了总PKM2和本已很低的PK活性水平，但矛盾的是，也限制了细胞在体外和体内的生长。这些结果表明，在胶质瘤中，丙酮酸激酶M的表达受到级别特异性的调节，但PK活性和PKM2表达的变化有助于GBM的生长。
Normal tissues express the M1 isoform of pyruvate kinase (PK) that helps generate and funnel pyruvate into the mitochondria for ATP production. Tumors, in contrast, express the less active PKM2 isoform, which limits pyruvate production and spares glycolytic intermediates for the generation of macromolecules needed for proliferation. Although high PKM2 expression and low PK activity are considered defining features of tumors, very little is known about how PKM expression and PK activity change along the continuum from low grade to high grade tumors, and how these changes relate to tumor growth. To address this issue, we measured PKM isoform expression and PK activity in normal brain, neural progenitor cells, and in a series of over 100 astrocytomas ranging from benign grade I pilocytic astrocytomas to highly aggressive grade IV glioblastoma multiforme (GBM). All glioma exhibited comparably reduced levels of PKM1 expression and PK activity relative to normal brain. In contrast, while grade I-III gliomas all had modestly increased levels of PKM2 RNA and protein expression relative to normal brain, GBM, regardless of whether they arose de novo or progressed from lower grade tumors, showed a 3–5 fold further increase in PKM2 RNA and protein expression. Low levels of PKM1 expression and PK activity were important for cell growth as PKM1 over-expression and the accompanying increases in PK activity slowed the growth of GBM cells. The increased expression of PKM2, however, was also important, because shRNA-mediated PKM2 knockdown decreased total PKM2 and the already low levels of PK activity, but paradoxically also limited cell growth in vitro and in vivo. These results show that pyruvate kinase M expression, but not pyruvate kinase activity, is regulated in a grade-specific manner in glioma, but that changes in both PK activity and PKM2 expression contribute to growth of GBM.
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肿瘤基因对神经元和星形胶质细胞的去分化会在小鼠中诱导神经胶质瘤。
DOI：
10.1126/science.1226929
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Friedmann-Morvinski D;Bushong EA;Ke E;Soda Y;Marumoto T;Singer O;Ellisman MH;Verma IM
通讯作者：
Verma IM
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
11.2
作者：
Chen M;Zhang J;Manley JL
通讯作者：
Manley JL
影响因子：
64.5
作者：
Chen J;McKay RM;Parada LF
通讯作者：
Parada LF
影响因子：
11.2
作者：
Chinnaiyan, Prakash;Kensicki, Elizabeth;Gillies, Robert
通讯作者：
Gillies, Robert