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Calreticulin, a Molecular Chaperone in the Endoplasmic Reticulum, Modulates Radiosensitivity of Human Glioblastoma U251MG Cells

¹ Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute; ² Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; and ³ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan

Requests for reprints: Yoshito Ihara, Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, 852-8523 Nagasaki, Japan. Phone: 81-95-849-7099; Fax: 81-95-849-7100; E-mail: y-ihara{at}net.nagasaki-u.ac.jp.

Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca²⁺-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca²⁺ homeostasis play a role in the modulation of apoptosis. In the present study, we found that the level of CRT was higher in neuroglioma H4 cells than in glioblastoma cells (U251MG and T98G), and was well correlated with the sensitivity to -irradiation. To examine the role of CRT in the radiosensitivity of malignant gliomas, the CRT gene was introduced into U251MG cells, which express low levels of CRT, and the effect of overexpression of CRT on the radiosensitivity was examined. The cells transfected with the CRT gene exhibited enhanced radiation-induced apoptosis compared with untransfected control cells. In CRT-overexpressing cells, cell survival signaling via Akt was markedly suppressed. Furthermore, the gene expression of protein phosphatase 2Ac (PP2Ac), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca²⁺. Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2Ac expression via altered Ca²⁺ homeostasis. These results show the novel mechanism by which CRT is involved in the regulation of radiosensitivity and radiation-induced apoptosis in malignant glioma cells. (Cancer Res 2006; 66(17): 8662-71)

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