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

Autor(en)

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

Abstrakt

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.

Organisation(en)

Institut für Analytische Chemie

Externe Organisation(en)

Medizinische Universität Wien, Universität für Bodenkultur Wien, Evercyte GmbH

Journal

Onco Target

Band

7

Seiten

27379-27393

Anzahl der Seiten

15

ISSN

1949-2553

DOI

https://doi.org/10.18632/oncotarget.8415

Publikationsdatum

05-2016

Peer-reviewed

Ja

ÖFOS 2012

301904 Krebsforschung, 106023 Molekularbiologie

Schlagwörter

ASJC Scopus Sachgebiete

Oncology

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/chronic-arsenic-trioxide-exposure-leads-to-enhanced-aggressiveness-via-met-oncogene-addiction-in-cancer-cells(a31d39f0-6a4d-437f-a82f-45dc1b05aa9f).html