The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism

BACKGROUND: By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. METHODS: Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. RESULTS: Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. CONCLUSION: We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

Quantitative Mapping of Mechanisms for Photoinitiated Coating Degradation

This work concerns the mathematical modeling of photoinitiated coating degradation. Using experimental evidence available, some of the most importantassumptions underlying existing models for the rmoset coatings are analyzed and suggestions for further work provided. A modeling approach that can be used toimplement the various effects of water on the degradation mechanisms of cross-linked coatings is also presented and experiments to test the approach are suggested. Additionally, simulations with an existing degradation model for an epoxy–amine coating are used to map the influence of model parameters on the lag time (i.e., the time passing prior to the onset of erosion) and the stable erosion rate. The simulation results can be used in the optimization of UV radiation-induced intercoat adhesion losses, which are often observed in multilayer coating systems based on top coated epoxy coatings. Finally, potential directions for future experimental research in the field are outlined