This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rohwer, N. Articles by Cramer, T. Search for Related Content PubMed PubMed Citation Articles by Rohwer, N. Articles by Cramer, T.

Hypoxia-Inducible Factor 1 Mediates Anoikis Resistance via Suppression of 5 Integrin

¹ Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and ² Freie Universität Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin, Germany; and ³ Klinik für Orthopädie und Unfallchirurgie, Abteilung für orthopädische Rheumatologie, Hufeland Klinikum, Mühlhausen, Germany

Requests for reprints: Thorsten Cramer, Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: 0049-30-450-553-022; Fax: 0049-30-450-553-902; E-mail: thorsten.cramer{at}charite.de.

Key Words: HIF-1 • anoikis • 5 integrin • fibronectin receptor • gastric cancer

The transcription factor hypoxia-inducible factor 1 (HIF-1) is abundantly expressed in the majority of human carcinomas and their metastases. HIF-1 controls central metastasis-associated pathways such as glycolysis, angiogenesis, and invasion. Functional inhibition of HIF-1 leads to impaired metastasis formation in murine tumor models. However, the precise molecular mechanisms underlying the metastasis-promoting role of HIF-1 have not been fully characterized. The ability of transformed epithelial cells to initiate the metastatic cascade relies on their ability to escape anoikis, a default program of apoptosis induction following loss of integrin anchoring to the extracellular matrix. Therefore, we addressed the function of HIF-1 in anoikis resistance and anchorage-independent growth. Inhibition of HIF-1 via RNA interference resulted in up-regulation of 5 integrin on the cell surface of human gastric cancer cells, whereas other integrins remained unaffected. Integrin 5 induction occurred at the level of transcription and was dependent on elevated intracellular superoxide in HIF-1-knockdown cells. HIF-1–deficient cells displayed significantly increased anoikis susceptibility due to up-regulated 5 integrin. Finally, colony formation in soft agar was shown to be dependent on HIF-1 as HIF-1–deficient cells displayed a 70% reduction in anchorage-independent proliferation. Results obtained by RNA interference could be entirely confirmed by application of the pharmacologic HIF-1-inhibitor 2-methoxyestradiol. Hence, our data argue for a pivotal role for HIF-1 in anoikis control via suppression of 5 integrin. HIF-1–inhibiting drugs might therefore offer an innovative strategy for antimetastatic cancer therapy. [Cancer Res 2008;68(24):10113–20]

This article has been cited by other articles:

				A. C. Roman, J. M. Carvajal-Gonzalez, E. M. Rico-Leo, and P. M. Fernandez-Salguero Dioxin Receptor Deficiency Impairs Angiogenesis by a Mechanism Involving VEGF-A Depletion in the Endothelium and Transforming Growth Factor-{beta} Overexpression in the Stroma J. Biol. Chem., September 11, 2009; 284(37): 25135 - 25148. [Abstract] [Full Text] [PDF]