Work

Cell type-dependent HIF1 α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells

Year: 2017

Type: article

Abstract: // Enikő Tátrai 1 , Alexandra Bartal 1, 2 , Alexandra Gacs 1 , Sándor Paku 3, 4 , István Kenessey 5, 6 , Tamás Garay 5 , Balázs Hegedűs 4, 7, 8 , Eszter Molnár 5 , Mihály T. Cserepes 1, 9, 10 , Zita Hegedűs 1 , Nóra Kucsma 9 , Gergely Szakács 9 and József Tóvári 1 1 Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary 2 Central Pharmacy, National Institute of Oncology, Budapest, Hungary 3 1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary 4 Tumor Progression Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary 5 2nd Department of Pathology, Semmelweis University, Budapest, Hungary 6 National Cancer Registry, National Institute of Oncology, Budapest, Hungary 7 Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria 8 Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany 9 Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary 10 Semmelweis University, Budapest, Hungary Correspondence to: 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 ABSTRACT 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 CoCl 2 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 CoCl 2 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.17806