Hypoxia attenuates the proinflammatory response in colon cancer cells by regulating IκB
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Kamila Müller-Edenborn1,2,*, Karolin Léger2,3,*, Jesus F. Glaus Garzon1,2,*, Carole Oertli1,2, Ali Mirsaidi2,4, Peter J. Richards2,4, Hubert Rehrauer5, Patrick Spielmann1,2, David Hoogewijs1,2, Lubor Borsig1,2,*, Michael O. Hottiger2,3,* and Roland H. Wenger1,2,*
1 Institute of Physiology, University of Zurich, Zurich, Switzerland
2 Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
3 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland
4 Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland
5 Functional Genomics Center, University of Zurich, Zurich, Switzerland
* The authors have contributed equally to this work
Roland H. Wenger, email:
Keywords: inflammatory bowel disease, lipopolysaccharide, NF-κB, tissue oxygenation, tumor hypoxia
Received: September 09, 2014 Accepted: April 10, 2015 Published: April 29, 2015
Two main features common to all solid tumors are tissue hypoxia and inflammation, both of which cause tumor progression, metastasis, therapy resistance and increased mortality. Chronic inflammation is associated with increased cancer risk, as demonstrated for inflammatory bowel disease patients developing colon cancer. However, the interplay between hypoxia and inflammation on the molecular level remains to be elucidated. We found that MC-38 mouse colon cancer cells contain functional hypoxic (HIF-1α) and inflammatory (p65/RelA) signaling pathways. In contrast to cells of the myeloid lineage, HIF-1α levels remained unaffected in MC-38 cells treated with LPS, and hypoxia failed to induce NF-κB. A similar regulation of canonical HIF and NF-κB target genes confirmed these results. RNA deep sequencing of HIF-1α and p65/RelA knock-down cells revealed that a surprisingly large fraction of HIF target genes required p65/RelA for hypoxic regulation and a number of p65/RelA target genes required HIF-1α for proinflammatory regulation, respectively. Hypoxia attenuated the inflammatory response to LPS by inhibiting nuclear translocation of p65/RelA independently of HIF-1α, which was associated with enhanced IκBα levels and decreased IKKβ phosphorylation. These data demonstrate that the interaction between hypoxic and inflammatory signaling pathways needs to be considered when designing cancer therapies targeting HIF or NF-κB.
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