Open AccessIncreased chemoresistance induced by inhibition of HIF‐prolyl‐hydroxylase domain enzymes
Author(s) -
Brökers Nils,
LeHuu Sinja,
Vogel Sabine,
Hagos Yohannes,
Katschinski Dörthe M.,
Kleinschmidt Malte
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01367.x
Subject(s) - etoposide , hela , gene knockdown , biology , hypoxia inducible factors , luciferase , cancer research , enzyme , transfection , microbiology and biotechnology , chemistry , cell , biochemistry , gene , chemotherapy , genetics
The hypoxia‐inducible factor (HIF) is the master regulator for oxygen‐dependent gene expression. The HIF signal transduction pathway can be manipulated by inhibiting the activity of the HIFα‐regulating prolyl‐4‐hydroxylase domain (PHD) enzymes. The consequence of inhibiting the PHD activity for chemoresistance was studied. Inhibiting the PHD activity with the 2‐oxoglutarate analog dimethyloxaloylglycine (DMOG) results in increased chemoresistance towards etoposide but not carboplatin in HeLa cells. Evidence for an etoposide‐specific resistance, which develops as a consequence of inhibiting the PHD activity, was further supported in a tetracycline‐inducible PHD2 knockdown HeLa cell model. The etoposide‐resistance was mediated by HIF‐1α as shown in mouse embryonic fibroblast HIF ‐1α +/+ and HIF ‐1α −/− cells. Decreased cellular cytotoxicity after etoposide treatment inversely correlated with a dimethyloxaloylglycine (DMOG)‐inducible, HIF‐1α‐dependent enhanced MDR‐1 expression and efflux activity as determined by RT‐PCR, immunoblots, and with the fluorescent dye DiOC2. Taken together, our data indicate that PHD inhibitors might increase chemoresistance of tumor cells in a HIF‐1‐dependent manner. ( Cancer Sci 2009; 101: xxx–xxx)