Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1alpha protein accumulation and vascular endothelial growth factor expression in human breast cancer cells.
OBJECTIVE
To investigate the effects of dauricine (Dau) on insulin-like growth factor-I (IGF-I)-induced hypoxia inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression in human breast cancer cells (MCF-7).


METHODS
Serum-starved MCF-7 cells were pretreated for 1 h with different concentrations of Dau, followed by incubation with IGF-I for 6 h. HIF-1alpha and VEGF protein expression levels were analyzed by Western blotting and ELISA, respectively. HIF-1alpha and VEGF mRNA levels were determined by real-time PCR. In vitro angiogenesis was observed via the human umbilical vein endothelial cell (HUVEC) tube formation assay. An in vitro invasion assay on HUVECs was performed.


RESULTS
Dau significantly inhibited IGF-I-induced HIF-1alpha protein expression but had no effect on HIF-1alpha mRNA expression. However, Dau remarkably suppressed VEGF expression at both protein and mRNA levels in response to IGF-I. Mechanistically, Dau suppressed IGF-I-induced HIF-1alpha and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway. In addition, Dau reduced IGF-I-induced HIF-1alpha protein accumulation by inhibiting its synthesis as well as by promoting its degradation. Functionally, Dau inhibited angiogenesis in vitro. Moreover, Dau had a direct effect on IGF-I-induced invasion of HUVECs.


CONCLUSIONS
Dau inhibits human breast cancer angiogenesis by suppressing HIF-1alpha protein accumulation and VEGF expression, which may provide a novel potential mechanism for the anticancer activities of Dau in human breast cancer.
Tang
Xu-dong
XD
Clinical Genetic Diagnosis Center, Zhongnan Hospital, Wuhan University, Wuhan, China.
Zhou
Xin
X
Zhou
Ke-yuan
KY
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014471:Umbilical Veins / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D044182:Benzylisoquinolines; D051793:Hypoxia-Inducible Factor 1; D011500:Protein Synthesis Inhibitors; D044005:Tetrahydroisoquinolines; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; C035934:dauricine