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


ABSTRACT: 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.

SUBMITTER: Ohoka N 

PROVIDER: S-EPMC5448626 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Ohoka Nobumichi N   Nagai Katsunori K   Shibata Norihito N   Hattori Takayuki T   Nara Hiroshi H   Cho Nobuo N   Naito Mikihiko M  

Cancer science 20170426 5


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 req  ...[more]

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