MELK inhibits cuproptosis in diffuse large B-cell lymphoma cells via the PI3K/mTOR/S6K-DLAT signaling axis

With a wide range of genetic characteristics and metabolic requirements, diffuse large B-cell lymphoma (DLBCL) is an extremely complex cancer. Although maternal embryonic leucine zipper kinase (MELK) has been linked to the development of tumors, its function in DLBCL and control of cuproptosis, a copper-dependent mechanism of cell deathproduce, is yet unknown. Hub genes in DLBCL were found using integrated bioinformatic analysis of the TCGA and GEO datasets. Using qRT-PCR, WB, cell viability, Transwell, and mitochondrial assays, MELK expression was examined in DLBCL cell lines (OCI-LY8, U2932, OCI-LY7) and normal B cells (GM12878). Functional analyses were conducted in selected DLBCL cell lines (OCI-LY7 and OCI-LY8) to accurately assess the biological roles of MELK. Elesclomol (15 nM) and copper chloride (CuCl₂, 10 µM) were used to induce cuproptosis, while DLAT overexpression and S6 kinase inhibition were used to clarify signaling processes. MELK expression was considerably elevated in DLBCL tissues and cell lines (P < 0.05). In addition to inducing mitochondrial malfunction, increasing reactive oxygen species, lowering the NADH/NAD⁺ ratio, and triggering intrinsic apoptosis, MELK silencing inhibited proliferation, migration, and invasion. MELK knockdown enhanced the sensitivity of cells to elesclomol-Cu treatment, which in turn induced cuproptosis and further reduced MELK expression. Mechanistically, MELK overexpression increased cell survival, elevated dihydrolipoamide S-acetyltransferase (DLAT), and triggered the PI3K/mTOR/S6K signaling pathway. On the other hand, MELK-mediated effects on cuproptosis and intracellular copper buildup were abolished by S6K suppression or DLAT overexpression. Through the PI3K/mTOR/S6K-DLAT axis, MELK imparts resistance to cuproptosis and increases DLBCL cell survival. MELK targeting may increase copper-induced cytotoxicity, offering a possible DLBCL treatment approach.