p38 Signaling-mediated hypoxia-inducible factor 1alpha and vascular endothelial growth factor induction by Cr(VI) in DU145 human prostate carcinoma cells.
Chromium(VI) (Cr(VI)) is widely used in industry and is a potent inducer of tumors in animals. The present study demonstrates that Cr(VI) induces hypoxia-inducible factor 1 (HIF-1) activity through the specific expression of HIF-1alpha but not HIF-1beta subunit and increases the level of vascular endothelial growth factor (VEGF) expression in DU145 human prostate carcinoma cells. To dissect the signaling pathways involved in Cr(VI)-induced HIF-1 expression, we found that p38 mitogen-activated protein kinase signaling was required for HIF-1alpha expression induced by Cr(VI). Neither phosphatidylinositol 3-kinase nor extracellular signal-regulated kinase activity was required for Cr(VI)-induced HIF-1 expression. Cr(VI) induced expression of HIF-1 and VEGF through the production of reactive oxygen species in DU145 cells. The major species of reactive oxygen species responsible for the induction of HIF-1 and VEGF expression is H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by Cr(VI) may be an important signaling pathway in the Cr(VI)-induced carcinogenesis.
Gao
Ning
N
Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia 26506-9300, USA.
Jiang
Bing-Hua
BH
Leonard
Stephen S
SS
Corum
Linda
L
Zhang
Zhuo
Z
Roberts
Jenny R
JR
Antonini
Jim
J
Zheng
Jenny Z
JZ
Flynn
Daniel C
DC
Castranova
Vince
V
Shi
Xianglin
X
D000975:Antioxidants / Q000378:metabolism; D002277:Carcinoma; D002374:Catalase / Q000378:metabolism; D002857:Chromium / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016877:Oxidants; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D002857:Chromium; C074702:chromium hexavalent ion; D006861:Hydrogen Peroxide; D002374:Catalase; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen