title: Selective cell death of p53-insufficient cancer cells is induced by knockdown of the mRNA export molecule GANP.
abstract: Cancer cells often contain p53 abnormalities that impair cell-cycle checkpoint progression and cause resistance to various anti-cancer treatments. DNA damage occurs at actively transcribed genes during G1-phase in yeast cells that have a deficient mRNA export capacity. Here, we show that germinal center-associated nuclear protein (GANP), a homologue of yeast Sac3 that is involved in mRNA export, is indispensable for ensuring the stability of human genomic DNA and that GANP knockdown causes apoptosis and necrosis of p53-insufficient cancer cells. Ganp small interfering RNA (siGanp)-induced DNA damage, accompanied by a decrease in the number of cells in S-phase, caused late apoptosis and necrosis in p53-insufficient cancer cells through both caspase-dependent and -independent mechanisms. siGanp effectively induced DNA damage leading to cell death in p53-insufficient cancer cells in vitro and protect the growth of cancer cells transplanted into immunocompromized mice, suggesting that siGanp has potential as a selective treatment for p53-insufficient cancer cells.
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Japan.
authors.forename: Suchada
authors.initials: S
authors.lastname: Phimsen
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Teruo
authors.initials: T
authors.lastname: Nakaya
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohta
authors.forename: Taiji
authors.initials: T
authors.lastname: Suda
authors.forename: Andri
authors.initials: A
authors.lastname: Rezano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kitabatake
authors.forename: Kulthida
authors.initials: K
authors.lastname: Vaeteewoottacharn
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Tone
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008854:Microscopy, Electron; D034443:RNA Transport / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000123:Acetyltransferases; C406825:MCM3AP protein, human; D020169:Caspases