Abstract
Hsp90 plays a key role in the stability and function of many cell-signaling molecules. We examined the effects of the Hsp90 inhibitors, geldanamycin (GA) and its analogue 17-allylamino-17-demethoxygeldanamycin (17AAG), on radiosensitivity and signal transduction pathways in human tumor cell lines. GA radiosensitized both SQ-5 and DLD-1 derived from lung carcinoma and colon adenocarcinoma, respectively, but potentiated X-ray sensitivity more in SQ-5, than in DLD-1 cells. Hsp90 binds to EGFR family, and its overexpression has been correlated with tumor resistance to radiation. We found that GA depleted EGFR and ErbB-2 in DLD-1 cells, and depleted only ErbB-2 in SQ-5 cells. Akt is thought to mediate many biological actions toward anti-apoptotic responses. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5, but not in DLD-1 cells after exposure to GA and X-ray irradiation. These findings suggest that GA enhances the radiation sensitivity of human tumor cells by inhibiting the EGFR signal transduction system and the Akt signaling pathway. We also showed that 17AAG, a less toxic derivative of GA, sensitized other squamous cell carcinoma cells to radiation. Hsp90 inhibitor should
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Machida, H;
Matsumoto, Y;
[1]
Shirai, M;
[2]
Kubota, N
[3]
- Ibaraki Prefectural University of Health Sciences, (Japan)
- Ibaraki University, (Japan)
- University of Minnesota Medical School, (Japan)
Citation Formats
Machida, H, Matsumoto, Y, Shirai, M, and Kubota, N.
Inhibition of signal transduction by the Hsp90 inhibitor sensitizes human tumor cells to radiation.
Australia: N. p.,
2003.
Web.
Machida, H, Matsumoto, Y, Shirai, M, & Kubota, N.
Inhibition of signal transduction by the Hsp90 inhibitor sensitizes human tumor cells to radiation.
Australia.
Machida, H, Matsumoto, Y, Shirai, M, and Kubota, N.
2003.
"Inhibition of signal transduction by the Hsp90 inhibitor sensitizes human tumor cells to radiation."
Australia.
@misc{etde_20520336,
title = {Inhibition of signal transduction by the Hsp90 inhibitor sensitizes human tumor cells to radiation}
author = {Machida, H, Matsumoto, Y, Shirai, M, and Kubota, N}
abstractNote = {Hsp90 plays a key role in the stability and function of many cell-signaling molecules. We examined the effects of the Hsp90 inhibitors, geldanamycin (GA) and its analogue 17-allylamino-17-demethoxygeldanamycin (17AAG), on radiosensitivity and signal transduction pathways in human tumor cell lines. GA radiosensitized both SQ-5 and DLD-1 derived from lung carcinoma and colon adenocarcinoma, respectively, but potentiated X-ray sensitivity more in SQ-5, than in DLD-1 cells. Hsp90 binds to EGFR family, and its overexpression has been correlated with tumor resistance to radiation. We found that GA depleted EGFR and ErbB-2 in DLD-1 cells, and depleted only ErbB-2 in SQ-5 cells. Akt is thought to mediate many biological actions toward anti-apoptotic responses. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5, but not in DLD-1 cells after exposure to GA and X-ray irradiation. These findings suggest that GA enhances the radiation sensitivity of human tumor cells by inhibiting the EGFR signal transduction system and the Akt signaling pathway. We also showed that 17AAG, a less toxic derivative of GA, sensitized other squamous cell carcinoma cells to radiation. Hsp90 inhibitor should be a potent therapeutic drug that can enhance the clinical effectiveness of radiation upon radioresistant tumor cells.}
place = {Australia}
year = {2003}
month = {Jul}
}
title = {Inhibition of signal transduction by the Hsp90 inhibitor sensitizes human tumor cells to radiation}
author = {Machida, H, Matsumoto, Y, Shirai, M, and Kubota, N}
abstractNote = {Hsp90 plays a key role in the stability and function of many cell-signaling molecules. We examined the effects of the Hsp90 inhibitors, geldanamycin (GA) and its analogue 17-allylamino-17-demethoxygeldanamycin (17AAG), on radiosensitivity and signal transduction pathways in human tumor cell lines. GA radiosensitized both SQ-5 and DLD-1 derived from lung carcinoma and colon adenocarcinoma, respectively, but potentiated X-ray sensitivity more in SQ-5, than in DLD-1 cells. Hsp90 binds to EGFR family, and its overexpression has been correlated with tumor resistance to radiation. We found that GA depleted EGFR and ErbB-2 in DLD-1 cells, and depleted only ErbB-2 in SQ-5 cells. Akt is thought to mediate many biological actions toward anti-apoptotic responses. GA also reduced the expression of Akt and phosphorylated Akt (pAkt) expression in SQ-5 cells. In addition, the ratio (%) of apoptotic cells and poly [ADP-ribose] polymerase cleavage increased in SQ-5, but not in DLD-1 cells after exposure to GA and X-ray irradiation. These findings suggest that GA enhances the radiation sensitivity of human tumor cells by inhibiting the EGFR signal transduction system and the Akt signaling pathway. We also showed that 17AAG, a less toxic derivative of GA, sensitized other squamous cell carcinoma cells to radiation. Hsp90 inhibitor should be a potent therapeutic drug that can enhance the clinical effectiveness of radiation upon radioresistant tumor cells.}
place = {Australia}
year = {2003}
month = {Jul}
}