title: Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus.
abstract: Glioblastoma multiforme (GBM) is the most aggressive and fatal brain tumor. GBM is resistant to chemotherapy and radiation. Recent studies have shown that glioma-initiating cells (GICs), which have characteristics of cancer stem cells, are responsible for the resistance to chemotherapy and radiation and regrowth. No effective therapy for GICs has been developed. Here we showed that D-isomer peptides (dPasFHV-p53C') consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C') induced the cell death of GICs. dPasFHV-p53C' was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3 μM completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C' but apoptosis was not. dPasFHV without p53C' showed the same effect as dPasFHV-p53C', suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C' reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C' could be a new method for the treatment of GBM.
authors.affiliation: Department of Molecular Physiology, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Fan-Yan
authors.initials: FY
authors.lastname: Wei
authors.forename: Taku-ichiro
authors.initials: T
authors.lastname: Hide
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Michiue
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takayama
authors.forename: Taku
authors.initials: T
authors.lastname: Kaitsuka
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Keishi
authors.initials: K
authors.lastname: Makino
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
authors.forename: Shiroh
authors.initials: S
authors.lastname: Futaki
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D016159:Tumor Suppressor Protein p53