Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells.
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 Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca(2+) 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 gamma-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 alpha (PP2Ac alpha), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca(2+). Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2Ac alpha expression via altered Ca(2+) 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.
Okunaga
Tomohiro
T
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.
Urata
Yoshishige
Y
Goto
Shinji
S
Matsuo
Takayuki
T
Mizota
Shingo
S
Tsutsumi
Keisuke
K
Nagata
Izumi
I
Kondo
Takahito
T
Ihara
Yoshito
Y
D017209:Apoptosis / Q000528:radiation effects; D037282:Calreticulin / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000528:radiation effects; D005909:Glioblastoma / Q000473:pathology* / Q000503:physiopathology / Q000532:radiotherapy; D006801:Humans; D011836:Radiation Tolerance; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D037282:Calreticulin; D011994:Recombinant Proteins