Ciliary neurotrophic factor receptor α subunit–modulated multiple downstream signaling pathways in hepatic cancer cell lines and their biological implications†

Abstract

UNLABELLED: Ciliary neurotrophic factor (CNTF) plays important roles in a variety of tissues including neural and non-neural systems, but the function of CNTF and its receptor (CNTFR) in liver remains unclear. In this study, we demonstrate that CNTFRalpha is expressed heterogeneously in normal human liver and hepatocellular carcinoma (HCC) specimens but not in hepatoblastoma specimens. We choose the CNTFRalpha(+)/CNTFRalpha(-) (CNTFRalpha positive/ CNTFRalpha negative) cell models of hepatic origin to study multiple downstream pathways of CNTFRalpha. We show that the presence of CNTFRalpha determines the temporal activation patterns of downstream signaling molecules and serves as a key modulator in regulating PI3K and AMP-activated protein kinase (AMPK) dynamically under CNTF stimulation, thus resulting in the increase of glucose uptake and translocation of glucose transporter 4 (GLUT4). Furthermore, CNTF-induced mitogen-activated protein kinase (MAPK) activation suppresses AMPK activity in the early phase of CNTF stimulation. Moreover, the protective role of CNTF against cell-cycle arrest is dependent on the presence of CNTFRalpha and is modulated by the glucose concentration of the culture medium. CONCLUSION: Our results demonstrate the importance of CNTFRalpha-mediated downstream signaling pathways and their functional implications in hepatic cancer cells, thus highlighting a better understanding of the biological roles of CNTFRalpha in human liver abnormalities, including metabolic diseases and hepatocarcinogenesis.