Abstract
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.
Highlights
Most mutations of human cancer are because of the activation of oncogenes and the loss of function of tumor suppressor genes, which commonly induce new blood vessels for tumors to grow beyond a few millimeters in diameter [1, 2]
Induction of Hypoxia-inducible factor 1 (HIF-1) Expression—To determine whether Cr(VI) could induce the expression of HIF-1 in DU145 cells, cells were exposed to Cr(VI) at different concentrations for 3 h, and total cellular protein extracts were prepared for immunoblot assays of HIF-1␣ and HIF-1 protein levels
PI3K and MAPK/Extracellular Signal-regulated Kinase Pathways Are Not Involved in Induction of HIF-1␣ by Cr(VI), and p38 MAPK Pathway Is Required for HIF-1␣ Expression—To determine whether PI3K signaling pathway was required for HIF-1␣ expression, DU145 cells were treated with LY294002 or wortmannin, inhibitors of PI3K
Summary
Most mutations of human cancer are because of the activation of oncogenes and the loss of function of tumor suppressor genes, which commonly induce new blood vessels (angiogenesis) for tumors to grow beyond a few millimeters in diameter [1, 2]. VEGF plays a key role in tumor progression and angiogenesis [2, 3] Both inhibition of VEGF expression and the function of its receptor decrease dramatically the tumor growth, invasion, and metastasis in animal models (18 –26). Tissue hypoxia is a major inducer for the expression of VEGF in tumors [27, 28] Somatic mutations such as oncogene Ras activation and tumor suppressor gene p53 inactivation increase VEGF expression (10, 29 –31). The present study investigates Cr(VI)-induced expression of HIF-1␣ and VEGF in DU145 human prostate carcinoma cells and the role of individual reactive oxygen species (ROS). (c) Are ROS species involved in Cr(VI)-induced HIF-1␣ and VEGF expression? (d) Which species among ROS play the critical roles in Cr(VI)induced HIF-1␣ and VEGF expression? The specific questions were as follows. (a) Is Cr(VI) able to induce HIF-1 and VEGF expression? (b) What are the up-stream signal pathways in Cr(VI)induced expression of HIF-1␣ protein? (c) Are ROS species involved in Cr(VI)-induced HIF-1␣ and VEGF expression? (d) Which species among ROS play the critical roles in Cr(VI)induced HIF-1␣ and VEGF expression?
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