FTY720 inhibits the Nrf2/ARE pathway in human glioblastoma cell lines and sensitizes glioblastoma cells to temozolomide.

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of various cytoprotective genes. Constitutive Nrf2 activation in many cancers enhances cell survival and resistance to anti-cancer drugs. Our previous studies have shown that FTY720 induced autophagy-related apoptosis and necroptosis and inhibited invasion and migration in human glioblastoma cells. However, whether FTY720 regulated Nrf2 in glioblastoma cells remained unclear. Cell viability assay, western blot, migration and invasion assay, short hairpin RNA (shRNA) were used. We found that FTY720 suppressed the protein and mRNA levels of Nrf2 in human U251MG and U87MG glioblastoma cells lines. In addition, the protein and mRNA levels of heme oxygenase-1 (HO-1) and NADPH:quinine oxidoreductase-1 (NQO-1), two representative target factors of Nrf2, also decreased upon FTY720 treatment. Knockdown of Nrf2 further promoted the anti-cancer effects of FTY720, while activation of Nrf2 exist the opposite effects. In addition, FTY720 significantly sensitized glioblastoma cells to temozolomide (TMZ). However, activation of Nrf2 essentially abolished the induced sensitivity by FTY720. Our results indicated the potential application of FTY720 in treatment of glioblastoma and demonstrated that inhibition of Nrf2 can enhance the sensitivity of cancer cells to chemotherapeutic drugs.