title: The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition.
abstract: OBJECTIVE
  The anti-malarial drug chloroquine (CQ) is also known as an autophagy inhibitor. Autophagy can promote tumor growth by fueling the necessary energy metabolism and inducing resistance to chemotherapy and/or irradiation in various human cancers. However, the role of autophagy in endometrial cancer has not yet been established. We investigated the anti-tumor effects and autophagy inhibition caused by CQ in endometrial cancer cells.
  
  
  METHODS
  Cell proliferation and cell cycle were assessed in response to CQ in six endometrial cancer cell lines by using an MTT assay and/or flow cytometry. To assess the level of autophagy, western blotting and an immunofluorescence assay were used to measure LC3 expression. The effects of knockdown of either ATG5 or ATG7, both of which are indispensable for induction of autophagy, were assessed via an MTT assay. Sensitivity to CQ was compared between parental and cisplatin-resistant (CP-r) Ishikawa endometrial cancer cells.
  
  
  RESULTS
  CQ suppressed proliferation in all six endometrial cancer cell lines in a dose-dependent manner, whereas it increased the population of apoptotic cells. Inhibition of autophagy via knockdown of either ATG5 or ATG7 decreased the sensitivity to CQ. Additionally, sensitivity to cisplatin was improved by knocking down ATG5 or ATG7. Finally, CP-r Ishikawa cells, with a high basal level of autophagy, were more sensitive to CQ than parental Ishikawa cells.
  
  
  CONCLUSIONS
  Our data suggest that autophagy is involved in endometrial tumor growth and cisplatin resistance. Furthermore, our data support a therapeutic role for CQ in endometrial cancer cells with upregulation of autophagy.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: katsutoshi-tky@umin.ac.jp.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Miyasaka
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kashiyama
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tanikawa
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Arimoto
authors.affiliation: Kanagawa Health Service Association, Kanagawa 231-0021, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuramoto
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo 162-0052, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans
chemical_list: D000962:Antimalarials; D002738:Chloroquine; D002945:Cisplatin
keywords: Autophagy; Chemosensitivity; Chloroquine; Cisplatin; Endometrial cancer