Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation.

Abstract

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.

• Authors: Yapeng Ji, Chuanzhen Yang, Zefang Tang, Yongfeng Yang, Yonglu Tian, Hongwei Yao, Xi Zhu, Zeming Zhang, Jiafu Ji, Xiaofeng Zheng
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 15308 (05 18 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28516914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Isoenzymes
• Nuclear Proteins
• RNA, Small Interfering
• Reactive Oxygen Species
• TSPYL2 protein, human
• Tyrosine
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Doxycycline

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinogenesis (genetics, metabolism, pathology)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• DNA-Binding Proteins
• Doxycycline (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Glycolysis (drug effects, genetics)
• Humans
• Isoenzymes (genetics, metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactate Dehydrogenase 5
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Phenotype
• Phosphorylation
• Protein Binding
• Protein Processing, Post-Translational
• RNA, Small Interfering (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Tyrosine (metabolism)
• Xenograft Model Antitumor Assays