title: Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells.
abstract: Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer.
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors: Rachel J
authors: RJ
authors: Person
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors: Ntube N Olive
authors: NN
authors: Ngalame
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors: Ngome L
authors: NL
authors: Makia
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors: Matthew W
authors: MW
authors: Bell
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors: Michael P
authors: MP
authors: Waalkes
authors: Stem Cell Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address: tokare@niehs.nih.gov.
authors: Erik J
authors: EJ
authors: Tokar
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D001151:Arsenic / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms; D008668:Metallothionein / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000378:metabolism
chemical_list: D002273:Carcinogens; C117307:KRAS protein, human; C530099:MT1A protein, human; C491053:MT2A protein, human; D011518:Proto-Oncogene Proteins; D008668:Metallothionein; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D001151:Arsenic
keywords: Adaptation; Human lung cells; Inorganic arsenic; KRAS; Lung cancer; Transformation