BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death

Proteasome inhibitors, such as bortezomib and carfilzomib, are FDA approved for the treatment of hemopoietic cancers, but recent studies have shown their great potential for treatment of solid tumors. Bax Delta 2, a unique proapoptotic Bax isoform, promotes non-mitochondrial cell death and sensitizes cancer cells to chemotherapy. However, endogenous Bax Delta 2 proteins are unstable and susceptible to proteasomal degradation. Here, we screened a panel of proteasome inhibitors in colorectal cancer cells with different Bax statuses. We found that all proteasome inhibitors tested were able to block Bax Delta 2 degradation without affecting the level of Baxa or Bcl-2 proteins. Among the inhibitors tested, only bortezomib and carfilzomib were able to induce differential cell death corresponding to the distinct Bax statuses. Bax Delta 2-positive cells had a significantly higher level of cell death at low nanomolar concentrations than Baxa-positive or Bax-negative cells. Furthermore, bortezomib-induced cell death in Bax Delta 2-positive cells was predominantly dependent on the caspase 8/3 pathway, consistent with our previous studies. These results imply that Bax Delta 2 can selectively sensitize cancer cells to proteasome inhibitors, enhancing their potential to treat colon cancer and other solid tumors. (C) 2018 The Authors. Published by Elsevier Inc.