title: 12-Deoxyphorbol 13-palmitate inhibits the expression of VEGF and HIF-1α in MCF-7 cells by blocking the PI3K/Akt/mTOR signaling pathway.
abstract: Vascular endothelial growth factor (VEGF) is an essential component for angiogenesis, and hypoxia-inducible factor-1α (HIF-1α), which controls the switch of glycolytic and oxidative metabolism, activates the transcription of VEGF. 12-Deoxyphorbol 13-palmitate (DP) is a compound isolated from the roots of Euphorbia fischeriana, and has been revealed to possess anticancer activity. In the present study, we found that DP is an effective inhibitor of VEGF and HIF-1α in MCF-7 cells. DP markedly reduced cell viability as determined by MTT assay. ELISA, western blotting and RT-qPCR assays indicated that DP significantly decreased the protein and mRNA expression of VEGF and the protein expression of HIF-1α, while HIF-1α mRNA remained unchanged. In addition, the entrance of HIF-1α into the nucleus was blocked after DP treatment as detected by immunofluorescence analysis. In a further study, we proved that the effects mentioned above were associated with constitutive interference of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. DP effectively inhibited the phosphorylation of PI3K and its downstream factors p-Akt and p-mTOR, oppositely enhanced the expression of TSC1 (hamartin) and TSC2 (tuberin), which could be reversed by the co-treatment with the PI3K inhibitor wortmannin. Moreover, the addition of wortmanin further downregulated the protein levels of VEGF and HIF-1α. The results revealed that DP inhibited the expression of VEGF and HIF-1α through the PI3K/Akt/mTOR signaling pathway, confirming that DP may be a potential therapeutic candidate for breast cancer.
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Cong
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Han
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Liling
authors.initials: L
authors.lastname: Yue
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Dong
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, Jianhua, Qiqihar, Heilongjiang 161006, P.R. China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Liu
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D009389:Neovascularization, Pathologic; D010703:Phorbol Esters / Q000008:administration & dosage*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D000077191:Wortmannin
chemical_list: C582659:12-deoxyphorbol 13-palmitate; D000730:Androstadienes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010703:Phorbol Esters; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin