کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1931554 | 1050557 | 2010 | 5 صفحه PDF | دانلود رایگان |
The 70 kDa ribosomal S6 kinase 1 (p70S6K1), a downstream target of phosphoinositide 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK), is an important regulator of cell cycle progression, and cell proliferation. Recent studies indicated an important role of p70S6K1 in PTEN-negative and AKT-overexpressing tumors. However, the mechanism of p70S6K1 in tumor angiogenesis remains to be elucidated. In this study, we specifically inhibited p70S6K1 activity in ovarian cancer cells using vector-based small interfering RNA (siRNA) against p70S6K1. We found that knockdown of p70S6K1 significantly decreased VEGF protein expression and VEGF transcriptional activation through the HIF-1α binding site at its enhancer region. The expression of p70S6K1 siRNA specifically inhibited HIF-1α, but not HIF-1β protein expression. We also found that p70S6K1 down-regulation inhibited ovarian tumor growth and angiogenesis, and decreased cell proliferation and levels of VEGF and HIF-1α expression in tumor tissues. Our results suggest that p70S6K1 is required for tumor growth and angiogenesis through HIF-1α and VEGF expression, providing a molecular mechanism of human ovarian cancer mediated by p70S6K1 signaling.
Research highlights
► P70S6K1 regulates VEGF expression;
► P70S6K1 induces transcriptional activation through HIF-1α binding site;
► P70S6K1 regulates HIF-1α, but not HIF-1β protein expression;
► P70S6K1 mediates tumor growth and angiogenesis through HIF-1α and VEGF expression.
Journal: Biochemical and Biophysical Research Communications - Volume 398, Issue 3, 30 July 2010, Pages 395–399