Proteasome inhibitors represent a novel class of
anticancer agents that are used in the treatment of
hematologic malignancies and various solid
tumors. However, mechanisms underlying their anticancer actions were not fully understood. It has been reported that strong
14-3-3 protein expression is observed and associated with
tumor genesis and progression of
astrocytoma. In addition, global inhibition of 14-3-3 functions with a general 14-3-3 antagonist
difopein induces apoptosis of human
astrocytoma cells, validating 14-3-3 as a potential molecular target for anticancer therapeutic management. In the current study, for the first time we demonstrated that
proteasome inhibitors downregulated 14-3-3ε and 14-3-3θ/τ in U87 and SF295
glioma cells. Overexpression of 14-3-3ε and 14-3-3θ/τ significantly suppressed apoptosis of human
glioma cells induced by
proteasome inhibitors. We also demonstrated that
MG132 activated ASK1 and siASK1 compromised the MG132-induced apoptosis of
glioma cells. Furthermore, overexpression of 14-3-3ε and 14-3-3θ/τ markedly suppressed activation of ASK1. Collectively, the current study supported that
proteasome inhibitors, at least in part, caused cytotoxicity of
glioma cells via downregulation of 14-3-3ε and 14-3-3θ/τ and subsequent activation of ASK1.