title: The single N-glycan deletion mutant of soluble ErbB3 protein attenuates heregulin β1-induced tumor progression by blocking of the HIF-1 and Nrf2 pathway.
abstract: It has been well documented that activation of the ErbB3-PI3K-Akt pathway is implicated in tumor survival and progression. We previously demonstrated that the single N-glycan deletion mutant of soluble ErbB3 protein (sErbB3 N418Q) attenuates heregulin β1-induced ErbB3 signaling. The active PI3K-Akt pathway augments the nuclear accumulation of hypoxia inducible factor (HIF)-1α, which activates the transcription of many target genes and drives cancer progression. In this study, we focused on the effects of sErbB3 N418Q mutant on nuclear accumulation of HIF-1α. Pretreatment with the sErbB3 N418Q mutant suppressed heregulin β1-induced HIF-1α activation in MCF7 cells. Similar results were also obtained in other breast cancer cell lines, T47D and BT474. Interestingly, these suppressive effects were not observed with the sErbB3 wild type. In addition, pretreatment with the sErbB3 N418Q mutant suppressed the cell migration of MCF7 cells induced by heregulin β1. Furthermore, incubation with heregulin β1 also induced the nuclear accumulation of Nrf2, and this effect was also reduced by the sErbB3 N418Q mutant, but not the sErbB3 wild type. These findings indicated that the sErbB3 N418Q mutant suppressed malignant formation of cancer cells by blocking of the HIF-1α and Nrf2 pathways.
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan. Electronic address: rinataka0429@gmail.com.
authors.forename: Rina
authors.initials: R
authors.lastname: Takamiya
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ariki
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Hashimoto
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Biochemistry, Sapporo Medical University School of Medicine, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuroki
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D061986:MCF-7 Cells; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D017354:Point Mutation; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020890:Neuregulin-1; C087230:heregulin beta1; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: ErbB; HIF-1; Heregulin β1; Nrf2