Lysyl oxidase-like ۲ promotes the survival, migration, and ferroptosis of endometrial cancer cells by activating the phosphoinositide ۳-kinase/protein kinase B pathway

Objective(s): LOXL۲, known as Lysyl oxidase-like ۲, is classified as a lysyl oxidase (LOX) family member. However, its role and mechanism in endometrial cancer (EC) are unknown. Therefore, we aimed to investigate the potential role and mechanism of LOXL۲ in EC.Materials and Methods: The levels of LOXL۲ expression in EC tissues and normal adjacent tissues were evaluated by immunohistochemically (IHC) labeling. Following the dye application, ۳-(۴,۵-dimethylthiazol-۲-yl)-۲,۵-diphenyltetrazolium bromide (MTT) and Transwell methodologies were executed to evaluate the effects of LOXL۲ inhibition and up-regulation on the growth, programmed cell death, migration, and susceptibility to iron-dependent cell death of EC. Moreover, protein analysis through Western blotting and gene expression analysis using Real-time quantitative PCR (RT-qPCR) was employed to measure the levels of pertinent biomarkers.Results: LOXL۲ is highly expressed in both EC tissues and serum in vivo. Silencing LOXL۲ reduced EC cell proliferation and migration while increasing apoptosis in vitro. LOXL۲ silencing increased the ferroptosis-related proteins Solute Carrier Family ۷ Member ۱۱ (SLC۷A۱۱) and Ferritin Heavy Chain ۱ (FTH۱) while decreasing Glutathione Peroxidase ۴ (GPX۴) (both, P<۰.۰۰۱). Additionally, LOXL۲ silencing reduced the p-PI۳K and p-Akt protein expression, while LOXL۲ overexpression (OE-LOXL۲) elevated the p-PI۳K and p-Akt protein expression (both, P<۰.۰۰۱). Additionally, LOXL۲ silencing increases SLC۷A۱۱ and FTH۱ while decreasing GPX۴ (both P<۰.۰۰۱). LOXL۲ overexpression has the opposite effect. However, the LY۲۹۴۰۰۲ inhibitor restores SLC۷A۱۱ and FTH۱ expression while decreasing GPX۴ (P<۰.۰۰۱).Conclusion: Our research demonstrated that LOXL۲ might protect EC via phosphorylation by activating the PI۳K/AKT pathway.

کلیدواژه ها:

Apoptosis ، Cell Proliferation ، Endometrial neoplasms ، LOXL۲ protein ، Phosphorylation