The proteasome inhibitor MG-132 protects hypoxic SiHa cervical carcinoma cells after cyclic hypoxia/reoxygenation from ionizing radiation.
BACKGROUND
Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of radiation therapy. This study was designed to determine how varying cycles of hypoxia/reoxygenation affect the response of cervical carcinoma cells irradiated under oxic and hypoxic conditions and whether this could be modulated by proteasome inhibition.


METHODS
Plateau-phase SiHa cervical carcinoma cells in culture were exposed to varying numbers of 30-minute cycles of hypoxia/reoxygenation directly before irradiation under oxic or hypoxic conditions. 26S Proteasome activity was blocked by addition of MG-132. Clonogenic survival was measured by a colony-forming assay.


RESULTS
Under oxic conditions, repeated cycles of hypoxia/reoxygenation decreased the clonogenic survival of SiHa cells. This effect was even more pronounced after the inhibition of 26S proteasome complex. In contrast, under hypoxic conditions, SiHa cells were radioresistant, as expected, but this was increased by proteasome inhibition.


CONCLUSIONS
Proteasome inhibition radiosensitizes oxygenated tumor cells but may also protect tumor cells from ionizing radiation under certain hypoxic conditions.
Pajonk
Frank
F
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1714, USA. fpajonk@mednet.ucla.edu
Grumann
Thorsten
T
McBride
William H
WH
D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology*; D019610:Cytoprotection / Q000502:physiology / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007976:Leupeptins / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism / Q000528:radiation effects; D046988:Proteasome Endopeptidase Complex / Q000528:radiation effects; D061988:Proteasome Inhibitors; D011839:Radiation, Ionizing; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D010100:Oxygen