Oncotarget

Research Papers:

Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

Kushtrim Kryeziu _, Christine Pirker, Bernhard Englinger, Sushilla van Schoonhoven, Melanie Spitzwieser, Thomas Mohr, Wilfried Körner, Regina Weinmüllner, Koray Tav, Johannes Grillari, Margit Cichna-Markl, Walter Berger and Petra Heffeter

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Oncotarget. 2016; 7:27379-27393. https://doi.org/10.18632/oncotarget.8415

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Abstract

Kushtrim Kryeziu1,2, Christine Pirker1, Bernhard Englinger1, Sushilla van Schoonhoven1, Melanie Spitzwieser3, Thomas Mohr1, Wilfried Körner4, Regina Weinmüllner5, Koray Tav5, Johannes Grillari5,6, Margit Cichna-Markl3, Walter Berger1,2, Petra Heffeter1,2

1Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

2Research Platform “Translational Cancer Therapy Research”, Vienna, Austria

3Department of Analytical Chemistry, University of Vienna, Vienna, Austria

4Department of Environmental Geosciences, University of Vienna, Vienna, Austria

5Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Applied Life Sciences, Vienna, Austria

6Evercyte GmbH, Vienna, Austria

Correspondence to:

Walter Berger, e-mail: [email protected]

Keywords: arsenic trioxide, carcinogen, aggressiveness, resistance, Met

Received: February 03, 2016     Accepted: March 18, 2016     Published: March 28, 2016

Dedicated to Prof. Dr. Bernhard K. Keppler at the occasion of his 60th birthday

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.


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