title: Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells.
abstract: Heat shock protein 90 (Hsp90) is constitutively expressed at 2‑10‑fold higher levels in tumor cells compared to normal cells, suggesting that it may be critically important for tumor cell growth and survival. These features make Hsp90 a potential target for anticancer drug development. Inhibition of Hsp90 activity not only results in rapid degradation of Hsp90 client proteins but also induces apoptosis of various tumor cells. Hsp90 also plays an important role in autophagy. An Hsp90 inhibitor induces autophagy through inhibition of mTOR. It is still under debate whether chemotherapy‑induced autophagy in tumor cells is a protective response or is invoked to promote cell death. The aim of this study was to examine the effects of the Hsp90 inhibitor, geldanamycin (GA), on KTHOS osteosarcoma cells. We further examined whether a combination of GA and the autophagy inhibitor 3‑methyladenine (3‑MA) enhanced GA‑induced apoptosis in KTHOS cells. GA had an inhibitory effect on cell proliferation and inhibited the Akt/mTOR signaling pathway in KTHOS cells. GA alone induced autophagy and apoptosis in KTHOS cells, but treatment with a combination of GA and 3‑MA suppressed autophagy and induced apoptosis to a much greater extent than GA alone in these cells. It was considered that the autophagy inhibitor 3‑MA suppressed a protective mechanism induced by Hsp90 inhibitor in tumor cells and induced apoptosis. Therefore, the combination of an Hsp90 inhibitor and an autophagy inhibitor may be an effective treatment for osteosarcoma because this combination effectively induces apoptotic pathways.
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitora
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakamura
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamagami
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Horie
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D012516:Osteosarcoma / Q000473:pathology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C001277:geldanamycin