Dauricine inhibits insulin-like growth factor-Ⅰ-induced hypoxia inducible factor la protein accumulation and vascular endothelial growth factor expression in human breast cancer cells  

作　　者：Xu-dong TANG Xin ZHOU Ke-yuan ZHOU 

机构地区：[1]Clinical Genetic Diagnosis Center, Zhongnan Hospital, Wuhan University, Wuhan 430071, China [2]Department of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang 524023, China

出　　处：《Acta Pharmacologica Sinica》2009年第5期605-616,共12页中国药理学报（英文版）

基　　金：Acknowledgements This work was supported by the grants from the National Natural Science Foundation of China （No 30872944）, the Guangdong Administration of Traditional Chinese Medicine （No 2008166）, and the Department of Science and Technology of Dongguan （No 2008108101029）. We thank Prof Xiong-tai GUAN （Guangdong Medical College, Zhanjiang, China） for kindly providing Dau. We also thank Dr Anh D Le and Dr Qun-zhou ZHANG （Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, USA） for their technical assistance and strong support.

摘　　要：Aim： To investigate the effects of dauricine （Dau） on insulin-like growth factor-Ⅰ （IGF-Ⅰ）-induced hypoxia inducible factor 1α （HIF-1α） 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-1α and VEGF protein expression levels were analyzed by Western blotting and ELISA, respectively. HIF-1α 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-1α protein expression but had no effect on HIF-1α 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-1α and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway. In addition, Dau reduced IGF-Ⅰ-induced HIF-1α 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. Conclusion： Dau inhibits human breast cancer angiogenesis expression, which may provide a novel potential mechanism for by suppressing HIF-1α protein accumulation and VEGF the anticancer activities of Dau in human breast cancer.Aim： To investigate the effects of dauricine （Dau） on insulin-like growth factor-Ⅰ （IGF-Ⅰ）-induced hypoxia inducible factor 1α （HIF-1α） 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-1α and VEGF protein expression levels were analyzed by Western blotting and ELISA, respectively. HIF-1α 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-1α protein expression but had no effect on HIF-1α 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-1α and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway. In addition, Dau reduced IGF-Ⅰ-induced HIF-1α 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. Conclusion： Dau inhibits human breast cancer angiogenesis expression, which may provide a novel potential mechanism for by suppressing HIF-1α protein accumulation and VEGF the anticancer activities of Dau in human breast cancer.

关 键 词：DAURICINE ANGIOGENESIS insulin-like growth factor-Ⅰ hypoxia inducible factor 1α vascular endothelial growth factor 

分 类 号：R587.2[医药卫生—内分泌] R735.2[医药卫生—内科学]