title: Radiation-Induced RhoGDIβ Cleavage Leads to Perturbation of Cell Polarity: A Possible Link to Cancer Spreading.
abstract: The equilibrium between proliferation and apoptosis is tightly balanced to maintain tissue homeostasis in normal tissues and even in tumors. Achieving and maintaining such a balance is important for cancer regrowth and spreading after cytotoxic treatments. Caspase-3 activation and tumor cell death following anticancer therapy as well as accompanying cell death pathways are well characterized, but their association to homeostasis of cancerous tissue and tumor progression remains poorly understood. Here we proposed a novel mechanism of cancer spreading induced by caspase-3. RhoGDIβ, known as a direct cleavage substrate of caspase-3, is overexpressed in many epithelial cancers. The N-terminal-truncated RhoGDIβ (ΔN-RhoGDIβ) is accumulated in caspase-3-activated cells. Stable expression of ΔN-RhoGDIβ in HeLa cells did not induce apoptosis, but impaired directional cell migration in a wound-healing assay accompanied by a perturbed direction of cell division at the wound edge. Subcellular protein fractionation experiments revealed that ΔN-RhoGDIβ but not wild-type RhoGDIβ was present in the detergent-soluble cytoplasmic and nuclear fractions and preferentially associated with Cdc42. Furthermore, Cdc42 activity was constitutively inhibited by stable expression of ΔN-RhoGDIβ, resulting in increased radiation-induced compensatory proliferation linking to RhoA activation. Thus, ΔN-RhoGDIβ dominant-negatively regulates Cdc42 activity and contributes to loss of polarity-related functions. The caspase-3-cleaved RhoGDIβ is a possible determinant to promote cancer spreading due to deregulation of directional organization of tumor cell population and inhibition of default equilibrium between proliferation and apoptosis after cytotoxic damage. J. Cell. Physiol. 231: 2493-2505, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Life and Environmental Sciences, Department of Life Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Faculty of Life and Environmental Sciences, Department of Life Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Faculty of Life and Environmental Sciences, Department of Life Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hori
authors.affiliation: Faculty of Life and Environmental Sciences, Department of Life Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suga
authors.affiliation: Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Jikihara
authors.affiliation: Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugihara
authors.affiliation: Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Shimamoto
authors.affiliation: Radioisotope Research Center, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Mori
authors.affiliation: Research & Development Division, Pias Corporation, Kobe, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakaoji
authors.affiliation: Research & Development Division, Pias Corporation, Kobe, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hamada
authors.affiliation: Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Ota
authors.affiliation: Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Wiedemuth
authors.affiliation: Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
authors.affiliation: Faculty of Life and Environmental Sciences, Department of Life Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tatsuka
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000528:radiation effects; D002465:Cell Movement / Q000528:radiation effects*; D016764:Cell Polarity / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D021381:Protein Transport / Q000528:radiation effects; D011827:Radiation; D013347:Subcellular Fractions / Q000378:metabolism; D014965:X-Rays; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D053148:Caspase 3; D020764:cdc42 GTP-Binding Protein