The Role of the Ubiquitin Proteasome Pathway in Experimental Cancer Cachexia

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The first evidence that the ubiquitin/proteasome pathway plays a key role in muscle atrophy came from the observation that, while inhibition of cal-pain proteases and lysosomal proteases is responsible for the 10-20% reduction in intracellular pro-teolysis, ATP depletion produces much higher degrees of protein breakdown inhibition [8]. The availability of drugs specifically inhibiting protea-some proteolytic activities (i.e. proteasome inhibitors, such as lactacystin, peptide aldehydes, vinyl sulfones, and dipeptide boronic acid analogs)

allowed for in vivo inhibition of proteolysis in experimental models of diabetes, acidosis, sepsis, and denervation atrophy. The results further confirmed the role of the ubiquitin/proteasome pathway in physiological and pathological muscle protein degradation [9-11].

Upregulation of components of the ATP-ubiq-uitin-dependent pathway has also been reported in experimental models of CC. In 1994, Llovera et al. [12] showed a 500% increase of ubiquitin gene expression in the muscle of rats bearing the fast-growing, cachexia-inducing AH-130 ascites hepatoma. Similarly, Temparis et al. [13] showed that mRNA levels for ubiquitin, 14-kDa E2, and proteasome subunits C8-C9 increased in the tib-ialis anterior muscles and correlated with the enhancement of energy-requiring proteolysis in Yoshida-sarcoma-bearing rats. Costelli et al. [14] described a 650% increase in the mRNA for 2.4-kb ubiquitin, and a 130% increase in the mRNA for 1.2-kb ubiquitin in the gastrocnemius muscles of rats bearing the Yoshida hepatoma.

Animal models have also shown that muscle proteasomal activity, as measured by the cleavage of specific fluorogenic substrates, is significantly increased in CC. Indeed, Costelli et al. [15] demonstrated that at least CTL activity is significantly increased (+246 ± 39% with respect to controls) in the gastrocnemius muscle of AH-130 ascites-

hepatoma-bearing rats, giving the first demonstration that the previously documented modulations of mRNA expression [12-14] are indeed reflective of increased proteolytic activity. Those findings further confirmed the suggestion that muscle wasting in CC is, at least in part, a cytokine-driven phenomenon and that pro-inflammatory cytokines participate in the hyperactivation of intracellular systems involved in protein degradation. In fact, anticytokine treatment with pentoxi-fylline (a drug that inhibits TNF-a synthesis) and/or with suramin (an anti-protozoal drug blocking the peripheral actions of several cytokines, including interleukin-6 and TNF-a) effectively reduced muscle protein loss by down-regulating the activity of the ubiquitin/proteasome system (Fig. 2) and calpains [15].

More recently, much interest has been devoted to the role of two ubiquitin ligases specifically expressed in striated muscle, namely, atrogin-1/MAFbx and MuRF-1, in the pathogenesis of muscle atrophy [16]. Overexpression of these ligases was initially demonstrated in denervation/dis-use-induced muscle atrophy [16], sepsis [17, 18], and during starvation. [19]. Subsequently, using cDNA microarrays, Lecker et al. [20] showed that a common set of genes, termed atrogins, were induced in muscles of fasted mice and in rats with cancer cachexia, streptozotocin-induced diabetes

Fig. 2. Proteasome-specific activity in the gastrocnemius muscles of AH-130 ascites-hepatoma-bearing rats (AH-130) treated with pen-toxyphilline (PTX), suramin (SUR), or both (PTX+SUR). Data are expressed as percent of controls ± SD. *, p < 0.01 vs controls; **, p < 0.05 vs AH-130; ***, p < 0.01 vs AH-130

Fig. 2. Proteasome-specific activity in the gastrocnemius muscles of AH-130 ascites-hepatoma-bearing rats (AH-130) treated with pen-toxyphilline (PTX), suramin (SUR), or both (PTX+SUR). Data are expressed as percent of controls ± SD. *, p < 0.01 vs controls; **, p < 0.05 vs AH-130; ***, p < 0.01 vs AH-130

mellitus, or uraemia. Among the strongly induced genes, some, such as ubiquitin fusion proteins, polyubiquitins, several proteasome subunits, and ubiquitin ligases, were related to protein degradation. The concept that ubiquitin ligases play a pivotal role in muscle atrophy was confirmed by the finding that mice knocked-out for atrogin genes do not develop denervation/disuse-induced muscle depletion [16].

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