E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation
E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation
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DOI：
10.1073/pnas.0913668107
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发表时间：
2010-01-12
影响因子：
11.1
通讯作者：
Moncada, Salvador
中科院分区：
文献类型：
--
作者：
Almeida, Angeles;Bolanos, Juan P.;Moncada, Salvador
已知细胞增殖伴随着糖酵解的活化。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，亚型3（PFKFB 3），是由E3泛素连接酶APC/C-Cdh 1，这也降解细胞周期蛋白降解。现在，我们在两种不同的细胞类型（肿瘤和非肿瘤），增殖和有氧糖酵解阻止Cdh 1的过表达和增强其沉默。此外，我们已经共表达Cdh 1与PFKFB 3-无论是野生型或突变体形式的泛在化APC/C-Cdh 1-或糖酵解酶6-磷酸果糖-1-激酶，并证明，而糖酵解是必不可少的细胞增殖，其启动在活性Cdh 1的存在下不会导致增殖。我们的实验表明，增殖反应，无论它是否发生在正常或肿瘤细胞，是依赖于APC/C-Cdh 1，激活增殖和糖酵解的活性降低。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意义。
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.