title: Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells.
abstract: USP7 is a deubiquitinating enzyme that involves the ubiquitin proteasome system (UPS) to maintain regulation of protein synthesis and degradation. The well-known substrate of USP7 is the Mdm2-p53 complex. In fact, several studies have reported that functional inhibition of USP7 induces cancer cell apoptosis through activation of p53. However, the contribution of oxidative or endoplasmic reticulum (ER) stress, which is commonly induced by inhibition of the UPS for USP7 inhibitor-mediated apoptosis in cancer cells, has not been investigated. In contrast to previous reports, we show that p53 is not critical during USP7 inhibitor-induced apoptosis in several cancer cells. Inhibition of deubiquitinating enzyme activities by USP7 inhibitors causes ER stress by accumulating polyubiquitinated proteins in cancer cells. Furthermore, we demonstrate that USP7 inhibitors increase intracellular reactive oxygen species and mainly cause cancer cell apoptosis. Taken together, our results reveal that oxidative and ER stress, rather than the Mdm2-p53 axis, mainly contributes to USP7 inhibitor-mediated apoptosis in cancer cells.
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Gibok
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Taek-In
authors.initials: TI
authors.lastname: Oh
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Ki Bum
authors.initials: KB
authors.lastname: Um
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Hyeshin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodamun-gu, Seoul 03722, Republic of Korea.
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Hong-Il
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Hackyoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Chungbuk, Republic of Korea. Electronic address: jhlim@kku.ac.kr.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: Apoptosis; ER stress; ROS; USP7 inhibitor