title: Therapeutic approach to target mesothelioma cancer cells using the Wnt antagonist, secreted frizzled-related protein 4: Metabolic state of cancer cells.
abstract: 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 24h 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 24h 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.
authors: Molecular Pharmacology Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Vanathi
authors: V
authors: Perumal
authors: Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Sebastian
authors: S
authors: Pohl
authors: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Kevin N
authors: KN
authors: Keane
authors: Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Frank
authors: F
authors: Arfuso
authors: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Philip
authors: P
authors: Newsholme
authors: Molecular Pharmacology Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors: Simon
authors: S
authors: Fox
authors: Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia. Electronic address: a.dharmarajan@curtin.edu.au.
authors: Arun
authors: A
authors: Dharmarajan
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D011518:Proto-Oncogene Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C000605506:GSK3B protein, human
keywords: Mesothelioma; Metabolism; Secreted frizzled-related protein 4; Wnt