Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect.
Hypoxia-inducible factor-1alpha (HIF-1alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1alpha, and the augmented HIF-1alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1alpha expression through an increase in ubiquitination, thereby accelerating HIF-1alpha degradation and inhibiting HIF-1alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1alpha activity. CA-S6K1 overexpression reversed HIF-1alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H(2)O(2) production, thereby preventing H(2)O(2)-enhanced HIF-1alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1alpha activity and HIF-1alpha-dependent tumor growth, which may result from a decrease in HIF-1alpha stability through S6K1 inhibition in combination with an H(2)O(2)-scavenging effect.
Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea. sgk@snu.ac.kr.
Woo Hyung
WH
Lee
Young Woo
YW
Kim
Jae Hoon
JH
Choi
Samuel Carroll
SC
Brooks
Mi-Ock
MO
Lee
Sang Geon
SG
Kim
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
D016166:Free Radical Scavengers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D025801:Ubiquitin; C026209:oltipraz; D006861:Hydrogen Peroxide; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000263:Adenylate Kinase; D046988:Proteasome Endopeptidase Complex