Hypoxia-induced alterations in the cellular redox status play a critical role in the development of
hypoxia-induced chemoresistance in
cancer cells. Human
biliverdin reductase (hBVR), an
enzyme involved in the conversion of
biliverdin into
bilirubin in
heme metabolism, was recently identified as an important cytoprotectant against oxidative stress and
hypoxia. However, the role of hBVR on
hypoxia-induced drug resistance has not been previously investigated. Using human
glioblastoma cell lines, we evaluated the potential role of hBVR in
hypoxia-induced drug resistance. We found that
hypoxia caused a significant increase in hBVR expression in
glioblastoma cells that was accompanied by chemoresistance. We also observed that
siRNA-based targeting of hBVR genes attenuated the
hypoxia-induced chemoresistance. Furthermore, knocking down hBVR induced a marked increase in the levels of intracellular
reactive oxygen species under hypoxic conditions, and the chemosensitizing effect of hBVR depletion was reversed by pretreatment with the
antioxidant N-acetylcysteine. These findings suggest that hBVR significantly contributes to the modulation of
hypoxia-induced chemoresistance of
glioblastoma cells by adjusting their cellular redox status.