Muscle catabolism in cancer and its attenuation by eicosapentaenic acid

Abstract

This work examines skeletal muscle catabolism in cancer and its attenuation by Eicosapentaenoic Acid (EPA).
In vivo studies in mice bearing a cachexia inducing murine colon
adenocarcinoma - MAC16, demonstrated an elevation in the gastrocnemius
muscle in the activity and expression of regulatory components of the
ubiquitin-proteasome proteolytic pathway. This was accompanied by an
accelerated loss of muscle tissue correlating with an increase in overall
weight loss, all of which were attenuated by prior daily dosing with EPA.
Recently a proteolysis inducing factor (PIF) has been isolated from the
MAC16 tumour, and from the serum and urine of cachectic cancer patients.
Previous studies have shown that PIF induces protein degradation in vitro,
and that this is possibly mediated through 15-hydroxyeicosatetraenoic acid
(15-HETE), a metabolite of the n-6 polyunsaturated fatty acid- arachidonate.
Employing the murine myoblast cell line C2C12, it was shown that both PIF
and 15-HETE increased protein degradation and expression of proteasome
subunits, processes which were again attenuated by prior incubation in EPA.
Similarly, in NMRI mice which had been fasted for 24hours, EPA and the
lipoxygenase inhibitor CV-6504 (but not structurally related fatty acids)
inhibited skeletal muscle proteolysis and expression of various proteasome
subunits, showing that firstly, EPA may be anti-cachexic partly through its
ability to influence 15-HETE production; and secondly that the effect is
specific for EPA as other fatty acids had no effect. Previous studies have
suggested the involvement of the signal transduction family NF_KB in
response to PIF in the liver. It has been demonstrated here that both PIF and
15-HETE increased nuclear translocation of NF_KB in the skeletal muscle of
tumour bearing mice and that EPA inhibited this process by its ability to
prevent the degradation of the NF_KB inhibitor protein I_KB. When an NF_KB
inhibitor was added to C2C12 myotubes, prior to the addition of PIF,
proteasome activity and protein degradation was inhibited, showing that
NF_KB is responsible for the increased proteasome activity and muscle
catabolism induced by PIF.
Taken together this work suggests that 15-hydroxyeicosatetraenoic acid is
the intracellular mediator for PIF induced protein degradation in skeletal
muscle and that elevated muscle catabolism is accomplished through an
increased functioning of the ubiquitin-proteasome pathway, a process
possibly mediated through an NF_KB dependent mechanism. The anticachectic
(and possibly the anti-tumourigenic) effects of EPA appear to be
achieved in part by its ability to inhibit the degradation of I_KB and possibly
by its ability to interfere with 15-HETE production.