SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib

We previously developed a hybrid small molecule SNIPER (Specific and Nongenetic IAP-dependent Protein ERaser) against transforming acidic coiled-coil-3 (TACC3), SNIPER(TACC3), that induces proteasomal degradation of TACC3 protein. In this study, we found that SNIPER(TACC3) induces cytoplasmic vacuolization derived from endoplasmic reticulum (ER) and paraptosis-like cell death selectively in Cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires X-linked inhibitor of Apoptosis protein (XIAP) induces ER stress, which results in ER-stress responses involving X-box binding protein-1 (XBP-1) and ER-derived vacuolization in Cancer cells. Importantly, inhibition of Proteasome enhanced the SNIPER(TACC3)-induced vacuolization, and the combination treatment of SNIPER(TACC3) and bortezomib exhibited a synergistic Anticancer activity in several Cancer cell lines. The induction of paraptosis-like cell death in Cancer cells by SNIPER(TACC3) could be applied to treat Cancer cells resistant to undergo Apoptosis by overexpression of XIAP.