Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells

Journal Article · Fri Oct 11 04:00:00 EDT 2013 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2013.09.025· OSTI ID:22242129

Richards, Alex K.; Kusumah, Ivonne; Perumal, Vanathi ^[1]; Bolitho, Erin M. ^[2]; Mutsaers, Steven E. ^[3]; Dharmarajan, Arun M. ^[4]

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1. Molecular Pharmacology Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA (Australia)
2. Western Australian Institute for Medical Research, The University of Western Australia Centre for Medical Research, Perth, WA (Australia)
3. Lung Institute of Western Australia, Centre for Asthma Allergy and Respiratory Research, University of Western Australia, Nedlands (Australia)
4. School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA (Australia)

Highlights: •Expression profile of Wnt pathway related genes in mesothelioma cells. •Differential expression of key Wnt pathway molecules and regulators. •Wnt3a stimulated mesothelioma growth whereas sFRP4 was inhibitory. •Targeting β-Catenin can sensitise mesothelioma cells to cytotoxic drugs. -- Abstract: Malignant mesothelioma (MM) is an uncommon and particularly aggressive cancer associated with asbestos exposure, which currently presents an intractable clinical challenge. Wnt signaling has been reported to play a role in the neoplastic properties of mesothelioma cells but has not been investigated in detail in this cancer. We surveyed expression of Wnts, their receptors, and other key molecules in this pathway in well established in vitro mesothelioma models in comparison with primary mesothelial cultures. We also tested the biological response of MM cell lines to exogenous Wnt and secreted regulators, as well as targeting β-catenin. We detected frequent expression of Wnt3 and Wnt5a, as well as Fzd 2, 4 and 6. The mRNA of Wnt4, Fzd3, sFRP4, APC and axin2 were downregulated in MM relative to mesothelial cells while LEF1 was overexpressed in MM. Functionally, we observed that Wnt3a stimulated MM proliferation while sFRP4 was inhibitory. Furthermore, directly targeting β-catenin expression could sensitise MM cells to cytotoxic drugs. These results provide evidence for altered expression of a number of Wnt/Fzd signaling molecules in MM. Modulation of Wnt signaling in MM may prove a means of targeting proliferation and drug resistance in this cancer.

• OSTI ID: 22242129
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 440; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DRUGS
IN VITRO
MESSENGER-RNA
MODULATION
NEOPLASMS
RECEPTORS