161P - DKK1 stabilization as a new malignant pleural mesothelioma therapeutic avenue

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Mesothelioma
Lung and other Thoracic Tumours
Presenter Alice Guazzelli
Citation Annals of Oncology (2017) 28 (suppl_2): ii56-ii58. 10.1093/annonc/mdx093
Authors A. Guazzelli1, E. Bakker2, F. Sotgia1, M. Listanti1, M. Krstic-Demonacos1, L. Mutti1
  • 1University of Salford, M5 4WT - Salford/GB
  • 2University of Salford, Salford/GB

Abstract

Background

Malignant Pleural Mesothelioma (MPM) is a cancer with a hypoxic microenvironment. Hypoxic niches favor “stemness” in cancer cell formation and therefore represent a novel therapeutic target. DKK1 (dickkopf) abrogates WNT signaling via lipoprotein-related protein 5/6 (LRP5/6) and secreted frizzled related proteins (sFRPs)-mediated interference. Doxycycline (DXC) has the potential to be a repositioned drug with potent inhibition of mitochondrial biogenesis, targeting cancer stem-like cell (CSC) generation. The aim of this study has been to assess the effect of DXC on DKK1 expression and MPM-CSC generation.

Methods

We have conducted a microarray analysis in MPM cell lines in normoxic and hypoxic (1% O2) conditions and on the basis of this experiment we have performed Western blot analysis of DKK1 and assessed MPM-CSCs generation (meso-spheres) in the same conditions before and following treatment with Doxycycline.

Results

Microarray analysis showed a significant increase in DKK1 following treatment with DXC (7.56 fold). However, hypoxic conditions showed progressive DKK1 degradation compared to normoxic conditions (as assessed by Western blotting), thus confirming the role of WNT signaling in hypoxia. Treatment with DXC promoted DKK1 stabilization in both normoxia and hypoxia and significantly prevented CSC generation via hampering DKK1 degradation in hypoxic conditions.

Conclusions

We have identified that both hypoxia and doxycycline exert differential cell-specific effects on DKK1 expression in cell monolayers, thus identifying DKK1 as a potential target for therapeutic development. DKK stabilization by DXC in hypoxic conditions paves the avenue of new therapeutic approaches aimed at WNT signaling regulation.

Clinical trial identification

N/A

Legal entity responsible for the study

Luciano Mutti\'s research group at the University of Salford

Funding

G.I.Me. – Gruppo Italiano Mesotelioma and University of Salford

Disclosure

All authors have declared no conflicts of interest.