Endothelial p70 S6 kinase 1 in regulating tumor angiogenesis.
The p70 S6 kinase 1 (p70S6K1) exerts its function in regulating protein synthesis, cell proliferation, cell cycle progression, and cell survival in response to growth factors and other cellular signals. But the direct effect of p70S6K1 in regulating tumor growth and angiogenesis remains to be elucidated. Here, we investigated the effect of p70S6K1 expressed in human dermal microvascular endothelial cells (HDMEC) in regulating cancer cell-inducing tumor growth and angiogenesis and found that HDMECs enhance cancer cell-induced tumor growth and angiogenesis. Constitutive activation of p70S6K1 in HDMECs is sufficient to enhance tumor growth and angiogenesis. Inhibition of p70S6K1 by its dominant-negative mutant in HDMECs interferes with tumor growth and angiogenesis, indicating that p70S6K1 activity in endothelial cells is required for regulating tumor angiogenesis. We found that p70S6K1 regulates hypoxia-inducible factor-1alpha (HIF-1alpha) expression in the human endothelial cells. Knockdown of HIF-1alpha in the endothelial cells decreases tumor growth and angiogenesis. These results show that p70S6K1 and HIF-1 play an important role in regulating the endothelial functions for inducing tumor growth and angiogenesis. This study helps to understand the role and molecular mechanism of p70S6K1 in regulating angiogenesis and tumor growth, and the role of endothelial p70S6K1/HIF-1 signaling in the regulation of tumor microenvironment and angiogenesis.
Liu
Ling-Zhi
LZ
Department of Pathology, Lab of Reproductive Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China.
Zheng
Jenny Z
JZ
Wang
Xin-Ru
XR
Jiang
Bing-Hua
BH
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D009368:Neoplasm Transplantation / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1