Abstract
Activation of MEK/ERK pathway generally results in stimulation of cell growth and confers a survival adavantage. The potential involvement of this pathway in cellular radiosensitivity, however, still remains unclear. The purpose of this study was to examine whether ERK pathway affects intrinsic radiosensitivity in mammalian cells. In order to inhibit MEK/ERK pathway, a MEK inhibitor, PD98059 was employed. When rat 3Y1 cells were treated with PD98059, at a concentration of 25uM, ionizing radiation-induced ERK activation at 6 Gy was almost completely inhibited. Cell growth was significantly suppressed even at 1uM. PD98059 treatment unexpectedly induced clonogenic radioresistance in a dose-dependent manner. Similar effect was observed by expression of kinase-deficient MEK, confirming the effect induced by PD98059 treatment. Radiation-induced apoptotic activity was significantly reduced in cells PD98059-treated cells as evaluated by PARP cleavage. The present study serves as a reminder that therapeutic interventions established based upon a general view could conversely work in certain conditions; characterization of individual tumors and a careful consideration are required. [J Radiat Res 44:421 (2003)]
