Reduced survivin expression and tumor cell survival during chronic hypoxia and further cytotoxic enhancement by the cyclooxygenase-2 inhibitor celecoxib.
Hypoxia is a characteristic feature of advanced solid tumors and may worsen prognosis. The development of tumor-targeted and hypoxia-inducible gene therapy vectors holds promise to selectively deliver and express suicidal or cytotoxic genes in hypoxic regions of tumors. In this regard, the promoter of the survivin gene, which encodes an anti-apoptotic protein that is strongly expressed in tumor tissue, has received attention because of its supposed inducibility by hypoxia. However, in our present study we demonstrate that treatment of various tumor cell lines with chronic hypoxia or with the hypoxia-mimetic CoCl(2) does not result in increased expression of survivin, but rather strongly suppresses this gene's activity. In contrast, expression of glucose-regulated protein 78 (GRP78/Bip) is substantially elevated under chronic hypoxia in vitro and in hypoxic areas of tumor tissue in vivo. Although tumor cells in general exhibit increased chemoresistance under hypoxic conditions, we found that hypoxic glioblastoma cells are more sensitive to killing by the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib, and this effect is reflected by further decreased expression of survivin. Intriguingly, 2,5-dimethyl-celecoxib (DMC), a close structural analog of celecoxib that lacks the ability to inhibit COX-2, is able to potently mimic the anti-tumor effects of its parent compound, indicating that inhibition of COX-2 is not involved in these processes. Taken together, our results caution against the use of survivin-based promoters to target hypoxic areas of tumors, but favor constructs that include the strongly hypoxia-inducible GRP78 promoter. In addition, our data introduce celecoxib as a drug with increased cytotoxicity against hypoxic tumor cells.
Kardosh
Adel
A
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Ave., HMR-405, Los Angeles, CA 90089-9094, USA.
Soriano
Nathaniel
N
Pyrko
Peter
P
Liu
Yen-Ting
YT
Jabbour
Mark
M
Hofman
Florence M
FM
Schönthal
Axel H
AH
D000068579:Celecoxib; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077022:Survivin
C107489:BIRC5 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000077022:Survivin; D003035:Cobalt; C018021:cobaltous chloride; D000068579:Celecoxib