Therapeutic approach to target mesothelioma cancer cells using the Wnt antagonist, secreted frizzled-related protein 4: Metabolic state of cancer cells

Journal Article · Mon Feb 15 04:00:00 EST 2016 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2016.02.008· OSTI ID:22746416

Perumal, Vanathi ^[1]; Pohl, Sebastian ^[2]; Keane, Kevin N. ^[3]; Arfuso, Frank ^[2]; Newsholme, Philip ^[3]; Fox, Simon ^[1]; Dharmarajan, Arun ^[2]

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1. Molecular Pharmacology Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA (Australia)
2. Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA (Australia)
3. School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA (Australia)

Malignant mesothelioma (MM) is an aggressive cancer, characterized by rapid progression, along with late metastasis and poor patient prognosis. It is resistant to many forms of standard anti-cancer treatment. In this study, we determined the effect of secreted frizzled-related protein 4 (sFRP4), a Wnt pathway inhibitor, on cancer cell proliferation and metabolism using the JU77 mesothelioma cell line. Treatment with sFRP4 (250 pg/ml) resulted in a significant reduction of cell proliferation. The addition of the Wnt activator Wnt3a (250 pg/ml) or sFRP4 had no significant effect on ATP production and glucose utilisation in JU77 cells at both the 24 and 48 h time points examined. We also examined their effect on Akt and Glycogen synthase kinase-3 beta (GSK3β) phosphorylation, which are both important components of Wnt signalling and glucose metabolism. We found that protein phosphorylation of Akt and GSK3β varied over the 24 h and 48 h time points, with constitutive phosphorylation of Akt at serine 473 (pAkt) decreasing to its most significant level when treated with Wnt3a+sFRP4 at the 24 h time point. A significant reduction in the level of Cytochrome c oxidase was observed at the 48 h time point, when sFRP4 and Wnt3a were added in combination. We conclude that sFRP4 may function, in part, to reduce/alter cancer cell metabolism, which may lead to sensitisation of cancer cells to chemotherapeutics, or even cell death. - Highlights: • Secreted frizzled-related protein 4 reduces mesothelioma cell proliferation. • Secreted frizzled-related protein 4 induces mesothelioma cell death. • Secreted frizzled-related protein 4's effects differ depending on the time course. • Secreted frizzled-related protein 4 interacts with Wnt3a in mesothelioma cells. • Secreted frizzled-related protein 4 has a biphasic effect on GSK3-β phosphorylation.

• OSTI ID: 22746416
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 341; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
ATP
CELL PROLIFERATION
CYTOCHROMES
GLUCOSE
GLYCOGEN
METABOLISM
METASTASES
NEOPLASMS
OXIDASES
PATIENTS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
REDUCTION
SERINE