title: Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells.
abstract: Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1α protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1α. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1α regulation and suggested its therapeutic potential in colon tumors.
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Central laboratory, The first people's hospital of Huzhou, Huzhou 313000, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Wang
authors.affiliation: Institute of Nautical Medicine, Nantong University, Nantong 226019, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D036702:Quassins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036702:Quassins; D017382:Reactive Oxygen Species; C020237:brusatol; D005947:Glucose