Abstract
BackgroundPatients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue.MethodsIn this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells.ResultsWF decreased the viability of C2C12 myotubes, especially at concentrations of 20–25 μg.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations.ConclusionThese results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model.
Highlights
Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue
The cells were analysed for protein synthesis using procedures adapted from White et al [28] with the following modifications: the myotubes were labelled with L[2,63H] phenylalanine (0.67 μCi.mmol-1 in Dulbecco's modified Eagle's medium (DMEM) added with cold phenylalanine (2 mmol.L-1) for 1 h
To determine whether the Walker factor' (WF) could have effects similar to proteolysis-inducing factor (PIF), we used the MTT, neutral red uptake (NRU) and nucleic acid content (NAC) assays to examine the effects of WF on C2C12 myotubes after treatment with various concentrations of WF for 24, 48 and 72 h
Summary
Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. Todorov et al [9] purified and characterised a 24 kDa sulphated glycoprotein from the cachexia-inducing MAC16 tumour and similar material was isolated from the urine of cachectic patients [9]. When this material was purified and injected into mice it produced a profound decrease in body weight, which was entirely due to loss of lean body mass [10]. Both biochemical [15] and histological analysis [16] support the notion that tumours are the source of PIF
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