Interferon alpha 2a down-regulates VEGF expression through PI3 kinase and MAP kinase signaling pathways.
An earlier report demonstrated that interferon alpha (IFN-alpha) inhibited tumor growth and recurrence in an MHCC97 xenograft model in nude mice by suppressing tumor angiogenesis rather than by inhibiting tumor cell proliferation. However, the underlying molecular mechanism was not fully elucidated. In this study, we demonstrated that IFN-alpha 2a could down-regulate VEGF expression both in mRNA and in protein levels, as well as down-regulating HIF-1 alpha mRNA expression in MHCC97 cells in vitro. A cDNA micro array analysis followed by Northern and Western blot analysis revealed that PI3 kinase and MAP kinase signaling pathways might be inhibited by IFN-alpha 2a. Blocking the function of IFN-alpha receptor with a specific peptide could eliminate the inhibitory effects of IFN-alpha 2a on VEGF expression. In addition, wortmannin and PD098059, respective inhibitors of the PI3 kinase and the MAP kinase signaling pathways, when used independently or in combination, could also down-regulate the VEGF synthesis and secretion in a similar pattern of IFN-alpha 2a. These observations may lead to the conclusion that IFN-alpha 2a could suppress VEGF synthesis and secretion by down-regulating HIF-1 alpha expression, via inhibition of the PI3 kinase and/or the MAP kinase signaling pathways.
Wu
Wei-Zhong
WZ
Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, 200032 Shanghai, P.R.China.
Sun
Hui-Chuan
HC
Shen
Yue-Fang
YF
Chen
Jie
J
Wang
Lu
L
Tang
Zhao-You
ZY
Iliakis
George
G
Liu
Kang-Da
KD
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases