title: Stress-induced phosphoprotein-1 maintains the stability of JAK2 in cancer cells.
abstract: Overexpression of stress-induced phosphoprotein 1 (STIP1) - a co-chaperone of heat shock protein (HSP) 70/HSP90 - and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Tsai
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Angel
authors.initials: A
authors.lastname: Chao
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Neu
authors.initials: CN
authors.lastname: Tsai
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan.
authors.forename: Shih-Che
authors.initials: SC
authors.lastname: Sue
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Shih
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chyong-Huey
authors.initials: CH
authors.lastname: Lai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D016889:Endometrial Neoplasms / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C079373:STIP1 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAK2; STIP1; cancer