MG132 as a
proteasome inhibitor that can induce apoptotic cell death in various cell types including
lung cancer cells. We investigated the cellular effects of
MG132 on human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition and death, and described the molecular mechanisms of
MG132 in HPF cell death. This agent dose-dependently inhibited the growth of HPF cells with an IC50 of approximately 20 µM at 24 h and induced cell death accompanied by the loss of mitochondrial membrane potential (
MMP; ∆Ψm) and an increase in
caspase-3 and -8 activities.
MG132 increased intracellular ROS levels and GSH-depleted cell numbers. However, all the tested
caspase inhibitors intensified HPF growth inhibition by
MG132 and
caspase-9 inhibitor also enhanced cell death and
MMP (∆Ψm) loss. Moreover, the administration of Bcl-2
siRNA augmented HPF cell death by
MG132 whereas p53, Bax,
caspase-3 and -8 siRNAs did not strongly affect cell death. In addition, each
caspase inhibitor and
siRNA differently affects ROS levels including O2•- regardless of cell growth inhibition and cell death levels.
Caspase-8 and -9 inhibitors increased the number of GSH-depleted cells in MG132-treated HPF cells. In conclusion,
MG132 induced growth inhibition and death in HPF cells in a
caspase-independent manner. The growth inhibition and death of HPF cells by
MG132 and/or each
caspase inhibitor or apoptosis-related
siRNA were not tightly related to the changes in ROS levels.