PMID- 21984483
OWN - NLM
STAT- MEDLINE
DCOM- 20120606
LR  - 20211020
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 125
IP  - 1
DP  - 2012 Jan
TI  - Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling 
      pathways and induces malignant transformation of human bronchial epithelial 
      cells.
PG  - 10-9
LID - 10.1093/toxsci/kfr256 [doi]
AB  - Cadmium is categorized as a human carcinogen especially involved in lung cancers. 
      Angiogenesis is considered a fundamental requirement for tumorigenesis, but the 
      mechanisms underlying the tumor angiogenesis induced by cadmium are poorly 
      understood. Using in vitro and in vivo models, we investigated the angiogenic 
      mechanisms of cadmium in human bronchial epithelial cells and tumor formation. 
      Our results demonstrated that cadmium (CdCl(2)) activated extracellular 
      signal-regulated kinases (ERK) and AKT signaling and elevated the expression of a 
      key downstream proangiogenic molecule hypoxia-inducible factor-1 (HIF-1) in 
      immortalized human lung epithelial BEAS-2B cells. Cadmium also induced reactive 
      oxygen species (ROS) production, which could be inhibited by ROS scavengers, 
      catalase and diphenyleneiodonium chloride. Inhibition of ROS generation also 
      attenuated ERK, AKT, p70S6K1 activation, and HIF-1alpha expression. Similar results 
      were obtained in normal human bronchial epithelial (NHBE) cells, showing that 
      cadmium induced HIF-1 expression via ROS/ERK/AKT signaling pathway. Furthermore, 
      cadmium induced vascular endothelial growth factor expression and transcriptional 
      activation through ROS, ERK, and AKT pathways. Finally, cadmium transformed human 
      bronchial epithelial cells in culture; the transformed cells induced tube 
      formation in vitro, angiogenesis on chicken chorioallantoic membrane, and formed 
      tumors in nude mice. Taken together, the results of this study provide 
      explanation for the role and molecular mechanisms of cadmium in promoting 
      angiogenesis in lung epithelial cells and malignant transformation and will be 
      helpful for improved occupational protection, prevention, as well as chemotherapy 
      of human lung cancers caused by heavy metal cadmium.
FAU - Jing, Yi
AU  - Jing Y
AD  - Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 
      Philadelphia, Pennsylvania 19107, USA.
FAU - Liu, Ling-Zhi
AU  - Liu LZ
FAU - Jiang, Yue
AU  - Jiang Y
FAU - Zhu, Yingxue
AU  - Zhu Y
FAU - Guo, Nancy Lan
AU  - Guo NL
FAU - Barnett, John
AU  - Barnett J
FAU - Rojanasakul, Yon
AU  - Rojanasakul Y
FAU - Agani, Faton
AU  - Agani F
FAU - Jiang, Bing-Hua
AU  - Jiang BH
LA  - eng
GR  - R01HL091456/HL/NHLBI NIH HHS/United States
GR  - P20 RR016440/RR/NCRR NIH HHS/United States
GR  - R01 LM009500/LM/NLM NIH HHS/United States
GR  - R21ES017237/ES/NIEHS NIH HHS/United States
GR  - R01CA109460/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111009
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 00BH33GNGH (Cadmium)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Bronchi/blood supply/*pathology
MH  - Cadmium/*toxicity
MH  - Cell Culture Techniques
MH  - Cell Line
MH  - Cell Transformation, Neoplastic/*chemically induced
MH  - Chick Embryo
MH  - Chorioallantoic Membrane/blood supply/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Epithelial Cells/*drug effects/enzymology/metabolism/pathology
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - Neoplasm Transplantation
MH  - Neovascularization, Pathologic/*chemically induced/enzymology/metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Reactive Oxygen Species/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Time Factors
MH  - Vascular Endothelial Growth Factor A/*biosynthesis
PMC - PMC3243743
EDAT- 2011/10/11 06:00
MHDA- 2012/06/07 06:00
PMCR- 2013/01/01
CRDT- 2011/10/11 06:00
PHST- 2011/10/11 06:00 [entrez]
PHST- 2011/10/11 06:00 [pubmed]
PHST- 2012/06/07 06:00 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - kfr256 [pii]
AID - 10.1093/toxsci/kfr256 [doi]
PST - ppublish
SO  - Toxicol Sci. 2012 Jan;125(1):10-9. doi: 10.1093/toxsci/kfr256. Epub 2011 Oct 9.