XTP8 Promotes Ovarian Cancer Progression by Activating AKT/AMPK/mTOR Pathway to Regulate EMT

Abstract

Ovarian cancer (OC) ranks as the fifth leading cause of cancer-related death in women. The main contributors to the poor prognosis of ovarian cancer are the high rates of recurrence and metastasis. Studies have indicated a crucial role for hepatitis B virus X Ag-Transactivated Protein 8 (XTP8), a protein containing the DEP domain, in various cellular processes, including cell growth, movement, and differentiation, across several types of cancers. However, the role of XTP8 in ovarian cancer remains unclear. We observed elevated expression of XTP8 in ovarian cancer. Silencing XTP8 inhibited cell proliferation, promoted apoptosis, and yielded contrasting results in cells overexpressing XTP8. Furthermore, XTP8 facilitated ovarian cancer invasion and migration, triggering epithelial-mesenchymal transition (EMT). Mechanistically, XTP8 silencing led to reduced phosphorylation levels of AKT, increased p-AMPK levels, and decreased p-mTOR levels, while XTP8 overexpression exerted the opposite effects. Additionally, the activation of p-AMPK rescued the promoting effect of XTP8 on EMT in ovarian cancer cell lines, indicating that XTP8 acts as an oncogene by modulating the AKT/AMPK/mTOR pathway. Through transcriptome sequencing to identify downstream targets of XTP8, we found that XTP8 influences the expression of Caldesmon (CALD1) at both transcriptional and translational levels. CALD1 can be considered a downstream target of XTP8. The collaborative action of XTP8 and CALD1 activates the AKT/AMPK/mTOR pathway, regulating EMT to promote ovarian cancer progression. Inhibiting this signaling axis might represent a potential therapeutic target for ovarian cancer.