Increased chemoresistance induced by inhibition of HIF-prolyl-hydroxylase domain enzymes.
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 HIFalpha-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-1alpha as shown in mouse embryonic fibroblast HIF-1alpha(+/+) and HIF-1alpha(-/-) cells. Decreased cellular cytotoxicity after etoposide treatment inversely correlated with a dimethyloxaloylglycine (DMOG)-inducible, HIF-1alpha-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.
Brökers
Nils
N
Department of Cardiovascular Physiology, Georg August University Göttingen, Göttingen, Germany.
Le-Huu
Sinja
S
Vogel
Sabine
S
Hagos
Yohannes
Y
Katschinski
Dörthe M
DM
Kleinschmidt
Malte
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D051379:Mice; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000600:Amino Acids, Dicarboxylic; D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005047:Etoposide; D016190:Carboplatin; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine