title: Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling.
abstract: Blocking dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is reported to alter proliferation and differentiation of various cells. Using salubrinal and guanabenz as an inhibitory agent of dephosphorylation of eIF2α, we addressed a question whether an elevated level of phosphorylated eIF2α attenuates malignant phenotypes of triple negative breast cancer cells (TNBCs) that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. We determined effects of salubrinal and guanabenz on in vitro phenotype of 4T1 mammary tumor cells and MDA-MB-231 human breast cancer cells and evaluated their effects on in vivo tumor growth using BALB/c mice injected with 4T1 cells. The results revealed that these agents block the proliferation and survival of 4T1 and MDA-MB-231 cells, as well as their invasion and motility. Silencing eIF2α revealed that eIF2α is involved in the reduction in invasion and motility. Furthermore, salubrinal-driven inactivation of Rac1 was suppressed in the cells treated with eIF2α siRNA, and treatment with Rac1 siRNA reduced cell invasion and motility. In vivo assay revealed that subcutaneous administration of salubrinal reduced the volume and weight of tumors induced by 4T1 cells. Collectively, the results indicate that these agents can attenuate malignant phenotype and tumor growth of breast cancer cells through the eIF2α-mediated Rac1 pathway. Since salubrinal and guanabenz are known to inhibit bone resorption, this study provides a potential use of eIF2α-mediated Rac1 regulation in suppressing the growth and metastasis of breast cancer.
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Minami
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tanjung
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Qiaoqiao
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Division of Medical Physics, Oncology Center, Osaka University Hospital, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koizumi
authors.affiliation: Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Sungsoo
authors.initials: S
authors.lastname: Na
authors.affiliation: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokota
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006143:Guanabenz / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects*; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D020830:rac1 GTP-Binding Protein; D006143:Guanabenz; D013890:Thiourea