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.
Highlights
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
No significant difference of Human coilin-interacting nuclear ATPase protein (hCINAP) levels was observed in four CRC stages (Supplementary Fig. 1e), while the hCINAP level was relatively higher in CMS2 with marked activation of Wnt and Myc signalings, and CMS3 with disordered metabolism (Supplementary Fig. 1f)
Our results suggest that CRCSCs obtain energy predominantly by glycolysis
Summary
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. 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. Epithelial cancer cells, including CRCSCs, often undergo the epithelial-to-mesenchymal transition (EMT), during which they lose cell–cell adhesion and cellular polarity, remodel the CSC microenvironment by degrading the extracellular matrix (ECM) and basement membrane, acquire stem cell-like, migratory and invasive properties, and develop resistance to apoptosis and chemotherapy[11], with downregulation of epithelial cadherin (E-cadherin) and upregulation of TWIST1, Zeb[1], Snail[1], vimentin and neural cadherin (N-cadherin)[12]. It has been reported that hCINAP is indispensable for Cajal body formation and supports cell viability[26,27]
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