Human AGK blocking peptide

Recent evidences show that acylglycerol kinase (AGK) expression is related to the occurrence and development of various human cancers. However, its roles in nasopharyngeal carcinoma (NPC) progression are still unclear. This work aims to explore the roles of AGK in NPC cell sternness. It was shown that AGK expression was higher in NPC tissues compared to the adjacent tissues. Online dataset analysis revealed that AGK expression was negatively correlated with the overall survival of NPC patients. Gain and loss of functional experiments demonstrated that AGK positively regulated the sternness of NPC cells, as evident by the change of the tumor sphereformation ability, ALDH1 activity and expression of sternness critical regulators. KEGG analysis were performed to determine the potential pathways of AGK involved in NPC cell sternness and showed that the PI3K/Akt pathway exhibited the most correlation with AGK expression. Further mechanistic studies confirmed that AGK promoted the sternness of NPC cells through activating the PI3K/Akt pathway, and thus enhancing beta-catenin accumulation in nucleus. This study demonstrates a novel AGK/PI3K/Akt/beta-catenin axis involving in NPC cell sternness.

JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple mutations within JAK2, which abrogate the function of JH2 and sustain JAK2 activation, are widely observed in hematological malignancies, comparable mutations have not been detected in solid tumors. How solid tumor cells override the autoinhibitory effect of the JH2 domain to maintain constitutive activation of JAK2/STAT3 signaling remains puzzling. Herein, we demonstrate that AGK directly interacted with the JH2 domain to relieve inhibition of JAK2 and activate JAK2/STAT3 signaling. Overexpression of AGK sustained constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly correlated with increased STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. These findings uncover a mechanism for constitutive activation of JAK2/STAT3 signaling in solid tumors and may represent a prognostic biomarker and therapeutic target.