title: Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells.
abstract: As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment.
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Kushtrim
authors.initials: K
authors.lastname: Kryeziu
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Englinger
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Sushilla
authors.initials: S
authors.lastname: van Schoonhoven
authors.affiliation: Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Spitzwieser
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Department of Environmental Geosciences, University of Vienna, Vienna, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Körner
authors.affiliation: Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Weinmüllner
authors.affiliation: Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.
authors.forename: Koray
authors.initials: K
authors.lastname: Tav
authors.affiliation: Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria.|Evercyte GmbH, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.affiliation: Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Margit
authors.initials: M
authors.lastname: Cichna-Markl
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D001152:Arsenicals; D010087:Oxides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077237:Arsenic Trioxide
keywords: Met; aggressiveness; arsenic trioxide; carcinogen; resistance