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Open AccessArticle

Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

by Chun-Han Hou 1, Feng-Ling Lin 2, Sheng-Mon Hou 3,*,† and Ju-Fang Liu 4,*,†
1
Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
2
Department of Dermatology, Sijhih Cathay General Hospital, Taipei 221, Taiwan
3
Department of Orthopedic Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
4
Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2014, 15(10), 17380-17395; https://doi.org/10.3390/ijms151017380
Received: 28 June 2014 / Revised: 12 August 2014 / Accepted: 16 September 2014 / Published: 29 September 2014
(This article belongs to the Section Biochemistry)
Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS. View Full-Text
Keywords: osteosarcoma; hyperthermia; endoplasmic reticulum (ER) stress; reactive oxygen species (ROS) osteosarcoma; hyperthermia; endoplasmic reticulum (ER) stress; reactive oxygen species (ROS)
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Hou, C.-H.; Lin, F.-L.; Hou, S.-M.; Liu, J.-F. Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells. Int. J. Mol. Sci. 2014, 15, 17380-17395.

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