Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA.
Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA.
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DOI：
10.1158/0008-5472.can-10-2513
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Manley JL
中科院分区：
文献类型：
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作者：
Chen M;Zhang J;Manley JL
与通过氧化磷酸化代谢葡萄糖以有效产生能量的正常细胞不同，肿瘤细胞优先通过有氧糖酵解代谢葡萄糖，这产生较少的能量，但有助于将更多的糖酵解代谢物掺入快速增殖所需的生物质中。从氧化磷酸化到有氧糖酵解的代谢转变部分是通过糖酵解酶丙酮酸激酶的剪接异构体的转换实现的。正常细胞表达丙酮酸激酶M1亚型（PKM 1），而肿瘤细胞主要表达M2亚型（PKM 2）。从PKM 1到PKM 2的转换促进有氧糖酵解，并为肿瘤形成提供选择性优势。PKM 1/M2亚型通过两个互斥外显子的选择性剪接产生。最近的一项研究表明，选择性剪接事件是由异质核核糖核蛋白（hnRNP）家族成员hnRNPA 1，hnRNPA 2和多聚嘧啶束结合蛋白（PTB;也称为hnRNPI）控制的。这些发现不仅提供了额外的证据表明，选择性剪接在肿瘤发生中起着重要作用，而且还揭示了hnRNP蛋白调节癌症细胞增殖的分子机制。
Unlike normal cells, which metabolize glucose by oxidative phosphorylation for efficient energy production, tumor cells preferentially metabolize glucose by aerobic glycolysis, which produces less energy but facilitates the incorporation of more glycolytic metabolites into the biomass needed for rapid proliferation. The metabolic shift from oxidative phosphorylation to aerobic glycolysis is partly achieved by a switch in the splice isoforms of the glycolytic enzyme pyruvate kinase. While normal cells express the pyruvate kinase M1 isoform (PKM1), tumor cells predominantly express the M2 isoform (PKM2). Switching from PKM1 to PKM2 promotes aerobic glycolysis and provides a selective advantage for tumor formation. The PKM1/M2 isoforms are generated through alternative splicing of two mutually exclusive exons. A recent study demonstrates that the alternative splicing event is controlled by heterogeneous nuclear ribonucleoprotein (hnRNP) family members hnRNPA1, hnRNPA2, and polypyrimidine tract binding protein (PTB; also known as hnRNPI). These findings not only provide additional evidence that alternative splicing plays an important role in tumorigenesis, but also shed light on the molecular mechanism by which hnRNP proteins regulate cell proliferation in cancer.