Introduction: Malignant mesothelioma (MM) is an aggressive cancer, characterized by a rapid progression, along with late metastasis and poor patient prognosis. It is resistant to many forms of standard anti-cancer treatment, and consequently development of new therapeutic strategies is important. Mechanisms of cancer cell metabolism are being re-visited by scientists, and may offer a means to not only to generate new diagnostic procedures, but to also develop new therapeutic targets and modalities in a variety of malignancies. In this study, we determined the effect of the Wnt pathway inhibitor, secreted frizzled receptor protein 4 (sFRP4) on mesothelioma cancer cell metabolism, via assessment of ATP production and glucose utilisation.
Methods: The effect of sFRP4 on cancer cell metabolism was examined using the mesothelioma cell line, JU77. Following treatment with Wnt3a (250 pg) in either the presence or absence of sFRP4 (250 pg), glucose concentration was determined in culture media using a fluorescent glucose oxidase enzyme assy. To assess ATP production, a recombinant luciferase assay was applied. Glucose results were calculated as a percentage of culture media at the beginning of the experiment (11.1 mM), while ATP results were calculated as a percentage of untreated control.
Results: It was found that Wnt3a enhanced both ATP production and glucose utilisation in JU77 cells. sFRP4 had no significant effect on ATP production, but slightly reduced JU77 glucose consumption. Interestingly, inclusion of Wnt3a along with sFRP4, prevented Wnt3a-mediated enhancement of mesothelioma cell metabolism, as observed through decreased ATP production and glucose consumption. In addition sFRP4 also decreased the cell migration and proliferation.
Conclusion: sFRP4 may function in part, to reduce/alter cancer cell metabolism, which may lead to sensitisation of cancer cells to chemotherapeutic regimen, or even cell death. Glycogen synthase kinase 3-beta (GSK-3b) is an important component of Wnt signalling and glucose metabolism, and our future work will probe the effect of sFRP4 on GSK-3b expression and activation.