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Int. J. Mol. Sci. 2013, 14(9), 19169-19185;

Involvement of Calcium-Mediated Reactive Oxygen Species in Inductive GRP78 Expression by Geldanamycin in 9L Rat Brain Tumor Cells

Department of Bioresources, Da-Yeh University, Changhua 515, Taiwan
Department of Life Science and Institute of Biotechnology, National Tsing Hua University, Hsinchu 300, Taiwan
School of Chinese Pharmaceutical Science and Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan
Department of Medical Research, Tungs' Taichung MetroHarbor Hospital, Taichung 435, Taiwan
Author to whom correspondence should be addressed.
Received: 24 July 2013 / Revised: 19 August 2013 / Accepted: 9 September 2013 / Published: 18 September 2013
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Treatment with geldanamycin (GA) leads to an increase in [Ca2+]c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca2+]c was significantly reduced in the presence of thapsigargin (TG) and ruthenium red (RR). GA-induced GRP78 expression is significantly decreased in the presence of BAPTA/AM, EGTA and RR, suggesting that the calcium influx from the extracellular space and intracellular calcium store oscillations are contributed to by the calcium mobilization and GRP78 expression induced by GA. The induced GRP78 expression is sensitive to added U73122 and Ro-31-8425, pinpointing the involvement of phospholipase C (PLC) and protein kinase C (PKC) in GA-induced endoplasmic reticulum (ER) stress. The antioxidants N-acetylcysteine (NAC), BAPTA/AM, EGTA and H7 also have significant inhibitory effects on ROS generation. Finally, neither H7 nor NAC was able to affect the calcium response elicited by GA. Our results suggest that the causal signaling cascade during GA-inducted GRP78 expression occurs via a pathway that connects PLC to cytoplasmic calcium increase, PKC activation and, then, finally, ROS generation. Our data provides new insights into the influence of GA on ER stress response in 9L RBT cells. View Full-Text
Keywords: geldanamycin; calcium; PKC; ROS; GRP78 geldanamycin; calcium; PKC; ROS; GRP78
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Sun, F.-C.; Shyu, H.-Y.; Lee, M.-S.; Lee, M.-S.; Lai, Y.-K. Involvement of Calcium-Mediated Reactive Oxygen Species in Inductive GRP78 Expression by Geldanamycin in 9L Rat Brain Tumor Cells. Int. J. Mol. Sci. 2013, 14, 19169-19185.

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