Abstract

Muscle wasting, a syndrome characterized by the disproportional loss of skeletal muscle, is a frequent complication in patients with cancer or other chronic diseases. Recent studies in vitro and in vivo have demonstrated that tumor cells produce and secrete cytokines such as TNF- α that are responsible for inhibition of differentiation of myoblast cells into multinucleated myotubes and thereby may prevent muscle repair in cancer patients. Activation of NF-κB triggered by TNF-α interaction with its receptor on muscle cells, is considered a major pathway through which cytokines lead to muscle wasting in cancer patients. Gene therapy offers a potential solution by modulating downstream events within muscle cells. In vitro models of muscle wasting can provide an important resource to understand which pathways to modulate and to test potential therapies. In our In vitro studies, we found that application of TNF-α results in apoptosis of primary C57 mouse myoblast cells at 3 days after treatment. IFN-γ, IL-1β and IL-6 do not lead to apoptosis of myoblast cells, but result in inhibition of myoblast differentiation at 20 ng/ml. In addition, the conditioned media from human prostate cancer cell lines (PC-3 and DU145P) and a human melanoma cell line (Mel) significantly inhibit the differentiation of myoblast cells. NF-κB activity was activated in treated myoblast cells compared to untreated or 293 cell culture supernatant-treated myoblast cells. However we found that myoblasts stably transfected with IKBSR, a mutant IKBα, or cellular FLICE/Caspase-8-inhibitory protein, cFLIP, inhibited NF-κB activation after treatment of myoblast cells with cytokines (TNF-α, IFN-γ, IL-1β or IL-6) or tumor cell conditioned media (PC-3, DU145P or Mel). Inhibition of NF-κB activation was associated with amelioration of the inhibition of muscle cell differentiation. To our knowledge, this is the first report that cFLIP, an important caspase-8-inhibitory protein is capable of inhibiting NF-κB activation and reducing inhibition of myoblast cell differentiation treated with PC-3, DU145P and Mel tumor media. The results encourage us to generate gene transfer virus vectors expressing IKBSR or cFLIP or both, and to determine whether IKBSR or cFLIP or both can ameliorate muscle wasting.

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