Open AccessSNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib
Author(s) -
Ohoka Nobumichi,
Nagai Katsunori,
Shibata Norihito,
Hattori Takayuki,
Nara Hiroshi,
Cho Nobuo,
Naito Mikihiko
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13198
Subject(s) - vacuolization , xiap , cancer cell , proteasome , endoplasmic reticulum , apoptosis , bortezomib , cancer research , proteasome inhibitor , programmed cell death , unfolded protein response , microbiology and biotechnology , cancer , mg132 , chemistry , biology , biochemistry , medicine , immunology , endocrinology , caspase , multiple myeloma
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.