Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y Leon, 37007 Salamanca, Spain.
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):738-41. doi: 10.1073/pnas.0913668107. Epub 2009 Dec 22.
Cell proliferation is known to be accompanied by activation of glycolysis. We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. We now show in two different cell types (neoplastic and nonneoplastic) that both proliferation and aerobic glycolysis are prevented by overexpression of Cdh1 and enhanced by its silencing. Furthermore, we have coexpressed Cdh1 with PFKFB3--either wild-type or a mutant form resistant to ubiquitylation by APC/C-Cdh1--or with the glycolytic enzyme 6-phosphofructo-1-kinase and demonstrated that whereas glycolysis is essential for cell proliferation, its initiation in the presence of active Cdh1 does not result in proliferation. Our experiments indicate that the proliferative response, regardless of whether it occurs in normal or neoplastic cells, is dependent on a decrease in the activity of APC/C-Cdh1, which activates both proliferation and glycolysis. These observations have implications for cell proliferation, neoplastic transformation, and the prevention and treatment of cancer.
细胞增殖伴随着糖酵解的激活。我们最近发现，糖酵解促进酶 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶同工酶 3（PFKFB3）被 E3 泛素连接酶 APC/C-Cdh1 降解，该酶也降解细胞周期蛋白。我们现在在两种不同的细胞类型（肿瘤和非肿瘤）中表明，过表达 Cdh1 可阻止增殖和有氧糖酵解，而沉默 Cdh1 则增强了它们的作用。此外，我们共表达了 Cdh1 与 PFKFB3-无论是野生型还是对 APC/C-Cdh1 介导的泛素化具有抗性的突变体-或与糖酵解酶 6-磷酸果糖-1-激酶，并证明尽管糖酵解对于细胞增殖是必需的，但在活性 Cdh1 的存在下其起始并不导致增殖。我们的实验表明，增殖反应，无论发生在正常细胞还是肿瘤细胞中，都依赖于 APC/C-Cdh1 活性的降低，该酶激活增殖和糖酵解。这些观察结果对细胞增殖、肿瘤转化以及癌症的预防和治疗具有重要意义。
