title: 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.
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nara
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Fujisawa, Kanagawa, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Cho
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Mikihiko
authors.identifier: http://orcid.org/0000-0003-0451-1337
authors.initials: M
authors.lastname: Naito
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054852:Small Molecule Libraries / Q000008:administration & dosage; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D054852:Small Molecule Libraries; C120551:TACC3 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
keywords: 
  XIAP
  ; Bortezomib; SNIPER(TACC3); cytoplasmic vacuolization; paraptosis