Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma
Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma
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DOI：
10.1038/ncomms3508
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发表时间：
2013-10-01
影响因子：
16.6
通讯作者：
Huang, Bo
中科院分区：
文献类型：
--
作者：
Ma, Ruihua;Zhang, Wanguang;Huang, Bo
糖异生是肝细胞的基本特征。这种糖异生活性是否也存在于恶性肝细胞中仍有待探索。更好地理解这一生物过程可能会带来新的治疗策略。在这里，我们表明小鼠或人类恶性肝细胞中不存在糖异生。我们发现，调节糖皮质激素活性的两种关键酶11β-HSD1和11β-HSD2在恶性肝细胞中反向表达，导致内源性糖皮质激素失活和糖异生作用丧失。在肝癌患者中，11β-HSD1和11β-HSD2的表达与预后和生存密切相关。地塞米松是合成糖皮质激素的活性形式，能够通过绕过 11 β-HSD 酶的异常调节来恢复恶性细胞的糖异生，从而产生肝癌的治疗效果。这些发现阐明了恶性肝细胞糖异生丧失的分子基础，并提出了新的治疗策略。
Gluconeogenesis is a fundamental feature of hepatocytes. Whether this gluconeogenic activity is also present in malignant hepatocytes remains unexplored. A better understanding of this biological process may lead to novel therapeutic strategies. Here we show that gluconeogenesis is not present in mouse or human malignant hepatocytes. We find that two critical enzymes 11 beta-HSD1 and 11 beta-HSD2 that regulate glucocorticoid activities are expressed inversely in malignant hepatocytes, resulting in the inactivation of endogenous glucocorticoids and the loss of gluconeogenesis. In patients' hepatocarcinoma, the expression of 11 beta-HSD1 and 11 beta-HSD2 is closely linked to prognosis and survival. Dexamethasone, an active form of synthesized glucocorticoids, is capable of restoring gluconeogenesis in malignant cells by bypassing the abnormal regulation of 11 beta-HSD enzymes, leading to therapeutic efficacy against hepatocarcinoma. These findings clarify the molecular basis of malignant hepatocyte loss of gluconeogenesis and suggest new therapeutic strategies.