title: Hypoxia attenuates the proinflammatory response in colon cancer cells by regulating IκB.
abstract: 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.
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Müller-Edenborn
authors.affiliation: Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
authors.forename: Karolin
authors.initials: K
authors.lastname: Léger
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Glaus Garzon
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Oertli
authors.affiliation: Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Ali
authors.initials: A
authors.lastname: Mirsaidi
authors.affiliation: Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Richards
authors.affiliation: Functional Genomics Center, University of Zurich, Zurich, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Rehrauer
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Spielmann
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Hoogewijs
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
authors.affiliation: Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
mesh_terms: D015687:Cell Hypoxia; D003110:Colonic Neoplasms; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C082161:lipopolysaccharide A
keywords: NF-κB; inflammatory bowel disease; lipopolysaccharide; tissue oxygenation; tumor hypoxia