Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation

Abstract

Indomethacin, a common nonsteroidal anti-inflammatory drug, has been shown to enhance radiation-mediated cellkilling effect through the activation of p38 mitogenactivated protein kinase (MAPK). We found that indomethacin strongly reduced the basal level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HT-29 human colon carcinoma cells. The inhibition of ERK1/2 by indomethacin was only observed in cells with high basal activities of ERK1/2 such as HT-29 cells, but not in cells with low basal activities, such as HeLa. Cell cycle analysis of HT-29 cells exposed with indomethacin showed a partial G1/S arrest and slow DNA synthesis. However, the treatment with NS398, a specific COX-1/2 inhibitor, failed to show any effect on cell cycle, indicating that the inhibition of COX-1/2 is not responsible for cell cycle arrest. Since U0126, a specific inhibitor for MEK1/2, also induced a partial G1/S arrest, the G1/S arrest induced by indomethacin is, at least in part, caused by the inhibition of ERK1/2. Cell proliferation of HT-29 was inhibited by the treatment of U0126 but not in HeLa cells, and the treatment of HT-29 cells with U0126 enhanced radiation sensitivity possibly due to the accumulation of cells in G1 phase. We found that 17-allylamino-17-demethoxygeldanamycin, a geldanamycin delivative, radiosensitized HT-29 cells at a relatively low dose of irradiation, and indomethacin and U0126 further enhanced this effect. Therefore, tumor cells with elevated ERK1/2 activity can be effectively sensitized to radiation treatment by a combinational inhibition of HSP90 and MAPK activity.

Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15

“…4A and 5A). These results were in agreement with previous findings that combined the inhibition of signalregulated kinases and HSP90-sensitized colon carcinoma cells to ionizing radiation (25). HSP90 has also been reported to modulate Akt kinase activity (26) and to compromise the DNA damage in response to radiation (27).…”

Indomethacin Induction of Metamorphosis from the Asexual Stage to Sexual Stage in the Moon Jellyfish,Aurelia aurita

“…Kobayashi et al 8) have reported that indomethacin reduced the basal level of ERK1/2 in human cells. We examined the possibility that indomethacin-induced strobilation could have resulted from the suppression of ERK activity by testing PD98059 and U0126, both inhibitors of the ERK signaling pathway, for their strobilation-inducing activity.…”

Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

“…The second effect was cellular growth inhibition by arresting cells at the S phase as like indomethacin. 29,30) Moreover, the effective concentrations of MW-03 used in the present study were at least 10-fold lower than that of indomethacin. Further experiments are needed in order to elucidate, for example, whether MW-03 exerts the same effects as NSAIDs.…”

“…30) Therefore, in an attempt to identify alternate/additional targets of MW-03 in LS174T cells, a cell-cycle analysis were performed with MW-03-treated LS174T cells using a flow cytometer. As shown in Fig.…”