title: Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor.
abstract: Although proteasome inhibitors such as bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a monotherapy for solid tumors, including colorectal cancer. We found in this study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of bortezomib on colon cancer cells containing wild-type p53, which underwent G2-M cell-cycle block and apoptosis. Further analysis indicated that tumor suppressor p53 was one of the proteins exported from nuclei upon proteasome inhibition, and in the presence of CRM1 inhibitor KPT330, nuclear p53, and expression of its target genes were increased markedly. Moreover, knockdown of p53 significantly reduced the synergistic cytotoxic action of bortezomib and KPT330 on p53+/+HCT116 cells. In mice, KPT330 markedly augmented the antitumor action of bortezomib against HCT116 xenografts as well as patient-derived xenografts that harbored functional p53. These results indicate that nuclear p53 is a major mediator in the synergistic antitumor effect of bortezomib and KPT330, and provides a rationale for the use of proteasome inhibitor together with nuclear export blocker in the treatment of colorectal cancer. It is conceivable that targeting nuclear exportation may serve as a novel strategy to overcome resistance and raise chemotherapeutic efficacy, especially for the drugs that activate the p53 system.Mol Cancer Ther; 16(4); 717-28. ©2016 AACR.
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Physiology, Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Yongwang
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Suzhou Institute of Systems Medicine, Center for Systems Medicine Research, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, P.R. China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Physiology, Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Chen-Ying
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Tong
authors.initials: T
authors.lastname: Yu
authors.affiliation: Crown Bioscience Inc., Santa Clara, California.
authors.forename: Yu-Yang
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Crown Bioscience Inc., Santa Clara, California.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Crown Bioscience Inc., Santa Clara, California.
authors.forename: Henry Q X
authors.initials: HQ
authors.lastname: Li
authors.affiliation: Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China. yyl@ism.cams.cn longcuidr@126.com.
authors.forename: Long
authors.initials: L
authors.lastname: Cui
authors.affiliation: Suzhou Institute of Systems Medicine, Center for Systems Medicine Research, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, P.R. China. yyl@ism.cams.cn longcuidr@126.com.
authors.forename: Yili
authors.initials: Y
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000069286:Bortezomib / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D061988:Proteasome Inhibitors; C495901:TP53 protein, human; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C585161:selinexor; D000069286:Bortezomib