Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells

Mori,Masaki; Hitora,Toshiaki; Nakamura,Osamu; Yamagami,Yoshiki; Horie,Ryosuke; Nishimura,Hideki; Yamamoto,Tetsuji

doi:10.3892/ijo.2014.2727

Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells

Authors:
- Masaki Mori
- Toshiaki Hitora
- Osamu Nakamura
- Yoshiki Yamagami
- Ryosuke Horie
- Hideki Nishimura
- Tetsuji Yamamoto
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Affiliations: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan
Published online on: October 23, 2014 https://doi.org/10.3892/ijo.2014.2727
Pages: 47-54
Copyright: © Mori et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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