title: Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation.
abstract: Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase-independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228-induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Motonobu
authors.initials: M
authors.lastname: Watanabe
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Imai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yui
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mizushima
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hiraumi
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kamitsuji
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Toyokuni
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
authors.forename: Toru
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001343:Autophagy; D002467:Cell Nucleus / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011379:Prognosis; D021381:Protein Transport; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D051033:Apoptosis Inducing Factor; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C087123:romidepsin