6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming
6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming
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DOI：
10.1016/j.biopha.2019.01.028
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发表时间：
2019-03-01
影响因子：
7.5
通讯作者：
Tong, Xianli
中科院分区：
文献类型：
--
作者：
Chen, Hu;Wu, Dongde;Tong, Xianli
更好地了解肝细胞癌（HCC）进展的分子机制对于制定治疗策略以克服HCC患者的化疗耐药至关重要。在这项工作中，我们发现6-磷酸葡萄糖酸脱氢酶（6PGD）是氧化戊糖磷酸途径的关键酶，对HCC的生长和存活很重要。与正常肝组织相比，我们证明了6PGD在HCC组织中的表达上调。6PGD过表达增加6PGD活性，促进正常肝细胞生长。相比之下，使用遗传和药理学方法靶向6PGD可抑制HCC的生长和存活。抑制6PGD的化疗药物联合使用比单独使用化疗药物更有效地抑制HCC的生长和生存。我们进一步发现，抑制6PGD可激活amp活化的蛋白激酶（AMPK）和乙酰辅酶A羧化酶1 (ACC1)，降低HCC中NADPH/NAD +和NADH水平，导致SIRT1活性降低和氧化应激。相反，AMPK的缺失显著消除了physon（一种选择性小分子6PGD抑制剂）降低NADPH/NAD +比例、生长和存活的作用，证实了AMPK在HCC细胞中作为抑制6PGD的相关上游激活剂的作用。我们的工作首次证明了6PGD的上调及其在HCC生长和存活中的关键作用。我们的研究结果表明，6PGD是克服HCC化疗耐药的有希望的治疗靶点。
Better understanding of the molecular mechanism involved in hepatocellular carcinoma (HCC) progression is essential for the development of therapeutic strategies to overcome chemoresistance in HCC patients. In this work, we show that 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is important for HCC growth and survival. Compared to normal liver tissues, we demonstrate that 6PGD expression is upregulated in HCC tissues. 6PGD overexpression increases 6PGD activity and promotes growth in normal liver cells. In contrast, targeting 6PGD using both genetic and pharmacological approaches inhibits HCC growth and survival. Combination of chemotherapeutic agents with 6PGD inhibition achieves greater efficacy in inhibiting HCC growth and survival than chemotherapeutic agent alone. We further show that inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase 1 (ACC1), and decreases level of NADPH/NAD + and NADH in HCC, leading to SIRT1 activity reduction and oxidative stress. Conversely, AMPK depletion significantly abolishes the effects of physcion (a selective small-molecule 6PGD inhibitor) in decreasing NADPH/NAD + ratio, growth and survival, confirming the role of AMPK as the relevant upstream activator with 6PGD inhibition in HCC cells. Our work is the first to demonstrate the upregulation of 6PGD and its critical involvement in growth and survival in HCC. Our findings suggest 6PGD as a promising therapeutic target to overcome chemoresistance in HCC.