Abstract
HSP90 combines many oncogene products and cell-signaling moleculues, and it plays a key role in the function and stability of these moleculues. We examined the effects of HSP90 inhibitors, geldanamycin (GA) on radiosensitivity and signal transduction pathways in normal and tumor cells derived from mouse and human. GA radiosensitized all tumor cells used in this experiment, but the degree of the radiosensitization were depend on cells. On the other hand, GA hardly sensitized normal cells to radiation. EGFR family that consisted of EGFR and ErbB-2 is client proteins of HSP90. We found that GA reduced EGFR and ErbB-2 levels in DLD-1, T-24, and normal cells, and reduced only ErbB-2 level in HMV-1 cells. GA also reduced the high basal levels of p-Akt in tumor cells, but normal cells have low basal levels of p-Akt. These findings suggest that GA enhances radiosensitivity of tumor cells by inhibiting PI3K/Akt signaling pathway. HSP90 inhibitor such as geldanamycin should be a potent therapeutic agent that can sensitize tumor cells, but not normal cells. [J Radiat Res 44:427 (2003)]
