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.

Identification of AK4 as a novel therapeutic target for serous ovarian cancer

“…In a mouse model of bladder cancer, AK4 shRNA transfection markedly inhibited tumor growth and metastasis compared with that in a scramble control group ( 20 ). AK4 is also a potential oncogene upregulated in metastatic colorectal cancer and exhibiting in vitro oncogenic properties ( 30 ). In addition, withaferin-A was identified as a potential agent for the treatment of metastatic lung cancer that could regulate AK4-associated gene expression ( 19 ).…”

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

“…In breast cancer, Jin et al revealed that Y10 phosphorylation elicited LDHA activation, promoting cancer cell invasion and enhancing anoikis resistance. Also in colorectal cancer, Ji et al found that human coilin–interacting nuclear ATPase protein (hCINAP) expression was positively correlated with the level of Y10 phosphorylated LDHA. The molecular mechanism is that hCINAP binds to the C‐terminal region of LDHA and depends on its own adenylate kinase activity to promote phosphorylation of LDHA catalyzed by fibroblast growth factor receptor 1 (FGFR1) at Y10 .…”

“…Also in colorectal cancer, Ji et al found that human coilin–interacting nuclear ATPase protein (hCINAP) expression was positively correlated with the level of Y10 phosphorylated LDHA. The molecular mechanism is that hCINAP binds to the C‐terminal region of LDHA and depends on its own adenylate kinase activity to promote phosphorylation of LDHA catalyzed by fibroblast growth factor receptor 1 (FGFR1) at Y10 . Furthermore, Fan et al found that direct phosphorylation of LDHA at Y10 and Y83 significantly enhanced LDHA tetramer formation and cofactor binding, resulting in a significant increase in lactate dehydrogenase activity.…”

Viability and mitochondrial bioenergetic functions in human colon cancer cells are not affected by treatment with peptides mtCPP1, UPF25, mtgCPP, and mtCPP1gHO

“…The AK-catalyzed phosphotransfer system plays a key role in the maintenance of energy homeostasis in well-differentiated cells with intermittent high-energy demand, such as neural, cardiac, and skeletal muscle cells [36]. It is upregulated in human CRC [37] with the total AK activity about 2 times higher than surrounding normal tissue [10]. The same was also observed in tumor cells of other histological types [38].…”