Role of HIF signaling on tumorigenesis in response to chronic low-dose arsenic administration.
Trivalent inorganic arsenic (arsenite, arsenic trioxide, As(III)) is a primary contaminant of groundwater supplies worldwide. As(III), marketed as trisenox, is also an FDA-approved agent to treat cancer It has been previously shown by our laboratory that As(III) administered at doses lower than a therapeutic anticancer dose results in an increase in tumor formation and blood vessel density of tumors. In this work it was found that chronic administration of As(III) approaching the EPA action level of 10 ppb, given in the drinking water of mice 5 weeks prior to B16-F10 melanoma implantation, increased the growth rate of primary tumors and the number of metastases to the lung. Further, levels of arsenic in the tumor and lung were found to be much greater than those in the blood and similar to pro-angiogenic As(III) doses. Levels of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) surrounding the blood vessels in the tumors of the As(III)-treated mice were also found to be increased. Exposure of isolated B16-F10 tumor cells to chronic (3 or 7 day) but not acute (4 h) low-dose As(III) was found to increase HIF-1alpha expression and secretion of VEGF. Finally, coadministration of an inhibitor of HIF (YC-1) or a VEGFR-2 kinase inhibitor (SU5416) was found to antagonize the pro-angiogenic effects of low-dose As(III). Together, these results suggest that chronic exposure to low-dose As(III) could stimulate growth of tumors through a HIF-dependent stimulation of angiogenesis.
Kamat
Chandrashekhar D
CD
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, USA.
Green
Dixy E
DE
Curilla
Susan
S
Warnke
Linda
L
Hamilton
Joshua W
JW
Sturup
Stefan
S
Clark
Callie
C
Ihnat
Michael A
MA
D000818:Animals; D001151:Arsenic / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply* / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009206:Myocardium / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000098:blood supply* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D001151:Arsenic