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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 vacuol...

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Detalles Bibliográficos
Autores principales: Ohoka, Nobumichi, Nagai, Katsunori, Shibata, Norihito, Hattori, Takayuki, Nara, Hiroshi, Cho, Nobuo, Naito, Mikihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448626/
https://www.ncbi.nlm.nih.gov/pubmed/28192613
http://dx.doi.org/10.1111/cas.13198
Descripción
Sumario: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.