title: Hypoxia upregulates Hsp90α expression via STAT5b in cancer cells.
abstract: Hsp90α is a molecular chaperone protein involved in the structural maturation of oncogenic signaling proteins. Hsp90 was recently identified as an anticancer target; various studies are ongoing to find ways for managing cancer through Hsp90α. However, this approach is limited by reported side-effects. Hypoxia is a hallmark of solid tumors, including those of breast cancer and the extent of tumor hypoxia is associated with resistance to treatment and poor prognosis. One of the major signaling pathways in cancer cells, the Jak2/STAT5b pathway, has been found to be closely correlated with hypoxia. The objective of this study was to investigate the role of Jak2/STAT5b in the regulation of Hsp90α expression so that Hsp90α targeting can be achieved indirectly by modulating the Jak2/STAT5b pathway. We examined the role of the Jak2/STAT5b pathway in the expression of Hsp90α under hypoxic conditions by immunoblotting, reporter gene assays, EMSA and RNA interference analysis. With the help of in vivo models, we also analyzed the expression of Hsp90α in different parts of solid tumor tissues. We found a close association between hypoxic stress and Hsp90α expression. We also determined that STAT5b regulates the expression of Hsp90α during hypoxic stimulation. Under hypoxic conditions the expression of Hsp90α and STAT5b were proportional. siRNA analysis and nucleotide analysis showed that the promoter of Hsp90α has a STAT5b binding domain. Our work confirmed that STAT5b is one of the transcription factors that regulate Hsp90α. We, therefore, concluded that under hypoxic conditions, the Jak2/STAT5b pathway regulates Hsp90α expression and it could serve as a promising target for the treatment of solid tumors.
authors.affiliation: Department of Pathology, School of Medicine, and Institute of                     Biomedical Science and Technology, Konkuk University Hospital, Seoul 143-701,                     Republic of Korea.
authors.forename: Se Hyung
authors.initials: SH
authors.lastname: Pak
authors.forename: Youn Hee
authors.initials: YH
authors.lastname: Joung
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Eun Joung
authors.initials: EJ
authors.lastname: Lim
authors.forename: Pramod
authors.initials: P
authors.lastname: Darvin
authors.forename: Yoon Mi
authors.initials: YM
authors.lastname: Na
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hong
authors.forename: Boram
authors.initials: B
authors.lastname: Lee
authors.forename: Tae Sook
authors.initials: TS
authors.lastname: Hwang
authors.forename: Taegyu
authors.initials: T
authors.lastname: Park
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Eon-Soo
authors.initials: ES
authors.lastname: Moon
authors.forename: Byung Wook
authors.initials: BW
authors.lastname: Cho
authors.forename: Kyung Do
authors.initials: KD
authors.lastname: Park
authors.forename: Hak Kyo
authors.initials: HK
authors.lastname: Lee
authors.forename: Ill-Min
authors.initials: IM
authors.lastname: Chung
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D049409:Luciferases, Firefly