Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation.
Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation.
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腺苷酸激酶 hCINAP 通过促进 LDHA 磷酸化来决定结直肠癌干细胞的自我更新
DOI：
10.1038/ncomms15308
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发表时间：
2017-05-18
影响因子：
16.6
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Ji Y;Yang C;Tang Z;Yang Y;Tian Y;Yao H;Zhu X;Zhang Z;Ji J;Zheng X
针对结直肠癌干细胞（CRCSC）的特定代谢表型是针对预后不良和复发的结直肠癌（CRC）患者的创新治疗策略。然而，CRCSC 的背景依赖性代谢特征仍不清楚。在这里，我们报告腺苷酸激酶 hCINAP 在 CRC 组织中过度表达。 hCINAP 的耗竭会抑制 CRCSC 的侵袭、自我更新、肿瘤发生和化疗耐药性，并导致间充质特征丧失。从机制上讲，hCINAP 与 LDHA（糖酵解的关键调节因子）的 C 端结构域结合，并依赖其腺苷酸激酶活性来促进 LDHA 在酪氨酸 10 处磷酸化，导致高度活跃的 Warburg 效应和较低的细胞 ROS 水平，并赋予 CRCSC 侵袭的代谢优势。此外，CRC患者中hCINAP表达与Y10磷酸化LDHA水平呈正相关。这项研究确定 hCINAP 是 CRCSC 代谢重编程的有效调节剂，也是 CRC 侵袭和转移的有希望的药物靶点。
Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is an innovative therapeutic strategy for colorectal cancer (CRC) patients with poor prognosis and relapse. However, the context-dependent metabolic traits of CRCSCs remain poorly elucidated. Here we report that adenylate kinase hCINAP is overexpressed in CRC tissues. Depletion of hCINAP inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs with a loss of mesenchymal signature. Mechanistically, hCINAP binds to the C-terminal domain of LDHA, the key regulator of glycolysis, and depends on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, resulting in the hyperactive Warburg effect and the lower cellular ROS level and conferring metabolic advantage to CRCSC invasion. Moreover, hCINAP expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study identifies hCINAP as a potent modulator of metabolic reprogramming in CRCSCs and a promising drug target for CRC invasion and metastasis.