Cell type-dependent HIF1 α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells
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Enikő Tátrai1, Alexandra Bartal1,2, Alexandra Gacs1, Sándor Paku3,4, István Kenessey5,6, Tamás Garay5, Balázs Hegedűs4,7,8, Eszter Molnár5, Mihály T. Cserepes1,9,10, Zita Hegedűs1, Nóra Kucsma9, Gergely Szakács9 and József Tóvári1
1Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary
2Central Pharmacy, National Institute of Oncology, Budapest, Hungary
31st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
4Tumor Progression Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
52nd Department of Pathology, Semmelweis University, Budapest, Hungary
6National Cancer Registry, National Institute of Oncology, Budapest, Hungary
7Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
8Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany
9Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
10Semmelweis University, Budapest, Hungary
József Tóvári, email: [email protected], [email protected]
Keywords: tumor cell motility, hypoxia, small GTPases, RhoA activation, metastasis
Received: November 09, 2016 Accepted: April 24, 2017 Published: May 11, 2017
Tumor hypoxia promotes neoangiogenesis and contributes to the radio- and chemotherapy resistant and aggressive phenotype of cancer cells. However, the migratory response of tumor cells and the role of small GTPases regulating the organization of cytoskeleton under hypoxic conditions have yet to be established. Accordingly, we measured the proliferation, migration, RhoA activation, the mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1α) and three small G-proteins, Rac1, cdc42 and RhoA in a panel of five human tumor cell lines under normoxic and hypoxic conditions. Importantly, HT168-M1 human melanoma cells with high baseline migration capacity showed increased HIF-1α and small GTPases expression, RhoA activation and migration under hypoxia. These activities were blocked by anti- HIF-1α shRNA. Moreover, the in vivo metastatic potential was promoted by hypoxia mimicking CoCl2 treatment and reduced upon inhibition of HIF-1α in a spleen to liver colonization experiment. In contrast, HT29 human colon cancer cells with low migration capacity showed limited response to in vitro hypoxia. The expression of the small G-proteins decreased both at mRNA and protein levels and the RhoA activation was reduced. Nevertheless, the number of lung or liver metastatic colonies disseminating from orthotopic HT29 grafts did not change upon CoCl2 or chetomin treatment. Our data demonstrates that the hypoxic environment induces cell-type dependent changes in the levels and activation of small GTPases and results in varying migratory and metastasis promoting responses in different human tumor cell lines.
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