TY - JOUR
T1 - Reduced survivin expression and tumor cell survival during chronic hypoxia and further cytotoxic enhancement by the cyclooxygenase-2 inhibitor celecoxib
AU - Kardosh, Adel
AU - Soriano, Nathaniel
AU - Pyrko, Peter
AU - Liu, Yen Ting
AU - Jabbour, Mark
AU - Hofman, Florence M.
AU - Schönthal, Axel H.
N1 - Funding Information:
We are grateful to Frank B. Furnari, Webster K. Cavenee (Ludwig Institute for Cancer Research, La Jolla, CA), and Guido Eibl (UCLA, Los Angeles, CA) for the various tumor cell lines. Survivin-luciferase and Grp78-luciferase constructs were kindly provided by Dario C. Altieri (Yale University, New Haven, CT) and Amy S. Lee (USC, Los Angeles, CA), respectively. The technical assistance of Farahnaz Talasazan is acknowledged. We thank the USC Glioma Research Group, in particular Thomas C. Chen, for fruitful discussions. Funding for this project was received from Accelerate Brain Cancer Cure and from the Margaret E. Early Medical Research Trust (to AHS).
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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.
KW - 2,5-dimethyl-celecoxib
KW - Celecoxib
KW - GRP78
KW - Hypoxia
KW - Survivin
UR - http://www.scopus.com/inward/record.url?scp=34548662444&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548662444&partnerID=8YFLogxK
U2 - 10.1007/s11373-007-9173-3
DO - 10.1007/s11373-007-9173-3
M3 - Article
C2 - 17440835
AN - SCOPUS:34548662444
SN - 1021-7770
VL - 14
SP - 647
EP - 662
JO - Journal of Biomedical Science
JF - Journal of Biomedical Science
IS - 5
ER -