Research Project
Grant-in-Aid for Young Scientists (B)
We have developed SNIPER compounds that induce selective degradation of target proteins. In this study, we designed and synthesized SNIPER(TACC3)s, which target the spindle regulatory protein TACC3. SNIPER(TACC3)s induce ubiquitylation and proteasomal degradation of TACC3 in cells. Mechanistic analysis indicated that APC/CCDH1 mediates the SNIPER(TACC3)-induced degradation of TACC3. SNIPER(TACC3) selectively induced apoptosis in cancer cells expressing a larger amount of TACC3 than normal cells.SNIPER(TACC3) also induced paraptosis-like cell death selectively in cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires XIAP induces ER-stress responses involving XBP-1 and ER-derived vacuolization in cancer cells. Importantly, inhibition of proteasome enhanced SNIPER(TACC3)-induced vacuolization, and combination treatment of SNIPER(TACC3) and bortezomib exhibited a synergistic anticancer activity in several cancer cell lines.
All 2017 2016 2015 2014
All Journal Article (6 results) (of which Int'l Joint Research: 5 results, Peer Reviewed: 6 results, Open Access: 2 results, Acknowledgement Compliant: 4 results) Presentation (12 results) Patent(Industrial Property Rights) (1 results)
Cancer Sci
Volume: 108 Issue: 5 Pages: 1032-1041
10.1111/cas.13198
J Biol Chem
Volume: 292 Issue: 11 Pages: 4556-4570
10.1074/jbc.m116.768853
Current Cancer Drug Targets
Volume: 16 Issue: 2 Pages: 136-146
10.2174/1568009616666151112122502
Methods Mol. Biol.
Volume: 1366 Pages: 549-560
10.1007/978-1-4939-3127-9_42
Bioorg. Med. Chem. Lett.
Volume: 25 Issue: 22 Pages: 5362-5366
10.1016/j.bmcl.2015.09.030
Cell Death Dis.
Volume: 5 Issue: 11 Pages: e1513-e1513
10.1038/cddis.2014.471