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

Nat Commun. 2017 May 18;8:15308. doi: 10.1038/ncomms15308.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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