Dissecting the possible role of p97 in muscle wasting during cancer

Half of patients with malignancies develops muscle wasting (i.e. cachexia) and aerobic exercise ameliorates their prognosis. The p97/VCP ATPase complex interacts with multiple binding proteins, estimated to be around 60, and mainly extracts proteins from multimeric structures. In particular, by interacting with Ufd1 or p47, it facilitates the rapid degradation of myofibrillar proteins during muscle atrophy caused by denervation or fasting. The aim of this study was to investigate if p97 (and through which of its adaptors) plays a role also during cancer cachexia and if this is modulated by physical exercise. To induce cachexia, we injected subcutaneously one million of colon adenocarcinoma (C26) cells in BALB/c mice. This tumour causes massive muscle depletion with premature death in mice. Interestingly, by microarrays, we found that 8 out of 58 p97-binding proteins were induced in cachectic Tibialis Anterior (TA) from C26 mice, while 10 were reduced (p<0.05). Further analyses of these adaptors are in progress. To understand if aerobic exercise improves cancer cachexia through p97 modulation in muscle, C26-bearing mice were run on treadmill for 5 days at 12 m/min and +15° inclination for 45 min/day. By Q-PCR or Western Blotting, we measured the expression of p97 and its main adaptor proteins (Ufd1, Ufd2, p47) in cachectic TA muscle. In vivo, we found that the mRNA levels of p97, Ufd1, Ufd2 and p47 were induced in cachectic TA muscle from C26-carrying mice, undergoing body weight loss (i.e. cachexia). Interestingly, treadmill exercise protected C26-bearing mice from gastrocnemius muscle loss, with no effect on tumour growth, and rescued the C26-induced upregulation of p97 transcripts but not of these adaptors in muscles. Our preliminary data suggest that p97/VCP ATPase may play a role in muscle wasting also during cancer in mice. It remains to address which adaptor may be implicated and whether shRNA for p97 is able to recapitulate the beneficial effects of aerobic exercise in vivo.