Institut for Biomedicin

Thomas Vorup-Jensen

Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Jessica Roos
  • ,
  • Sabine Grösch
  • ,
  • Oliver Werz
  • ,
  • Peter Schröder
  • ,
  • Slava Ziegler
  • ,
  • Simone Fulda
  • ,
  • Patrick Paulus
  • ,
  • Anja Urbschat
  • ,
  • Benjamin Kühn
  • ,
  • Isabelle Maucher
  • ,
  • Jasmin Fettel
  • ,
  • Thomas Vorup-Jensen
  • Matthias Piesche
  • ,
  • Carmela Matrone
  • ,
  • Dieter Steinhilber
  • ,
  • Michael J Parnham
  • ,
  • Thorsten J Maier

Canonical Wnt signaling is a highly conserved pathway with a prominent role in embryogenic development, adult tissue homeostasis, cell polarization, stem cell biology, cell differentiation, and proliferation. Furthermore, canonical Wnt signaling is of pivotal importance in the pathogenesis of a number of cancer types and crucially affects tumor initiation, cancer cell proliferation, cancer cell apoptosis, and metastasis. Reports over the last decade have provided strong evidence for a pathophysiological role of Wnt signaling in non-malignant classical inflammatory and neurodegenerative diseases. Although, several agents suppressing the Wnt pathway at different levels have been identified, the development of clinically relevant Wnt-inhibiting agents remains challenging due to selectivity and toxicity issues. Several studies have shown that long-term administration of non-steroidal anti-inflammatory drugs protects against colon cancer and potentially other tumor types by interfering both with the COX and the Wnt pathway. Our own studies have shown that non-steroidal anti-inflammatory drugs suppress Wnt signaling by targeting the pro-inflammatory enzyme 5-lipoxygenase which is the key enzyme pathophysiologically involved in the synthesis of leukotrienes. Furthermore, we found a direct link between the 5-lipoxygenase and Wnt signaling pathways, which is essential for the maintenance of leukemic stem cells. Accordingly, genetic and pharmacological inhibition of 5-lipoxygenase led to an impairment of Wnt-dependent acute and chronic myeloid leukemic stem cells. We believe that 5-lipoxygenase inhibitors might represent a novel type of Wnt inhibitor activating a potentially naturally occurring novel mechanism of suppression of Wnt signaling that is non-toxic, at least in mice, and is potentially well tolerated in patients.

OriginalsprogEngelsk
TidsskriftPharmacology & Therapeutics
Vol/bind157
Sider (fra-til)43-64
Antal sider22
ISSN0163-7258
DOI
StatusUdgivet - jan. 2016

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