Elevated levels of the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF), is associated with certain cancers. TNF is thought to be a major contributor of cancer cachexia, a syndrome characterized by extreme weight loss, resulting from the wasting of skeletal muscle and adipose tissues. It is estimated that a majority of cancer patients exhibit cachexia, and strikingly, nearly one third of cancer mortalities result from cachexia, rather than tumor burden. Although the effects of TNF in cancer cachexia have long been studied, to date, very few if any cytokine-inducible molecular targets have been identified that mediate skeletal muscle and fat degeneration. NF-kappaB is a transcription factor which is potently activated by TNF. Previously, we identified that NF-kappaB functions as a negative regulator of skeletal muscle differentiation. Recent results reveal that TNF-induced activation of NF-kappaB leads to the repressed expression of MyoD, a skeletal muscle-specific transcription factor considered the """"""""master switch"""""""" in the regulation of myogenic differentiation. It was also elucidated that TNF action requires additional signaling from the IFN- gamma pathway to elicit muscle wasting and that this degenerative process is completely prevented in the absence of NF-kappaB activity. Similar to skeletal muscle, very little is known at the molecular level about how TNF induces adipose tissue wasting. Preliminary data in this proposal demonstrate that TNF-induced fat loss correlates with a loss of C/EBP-alpha, a transcription factor whose expression is known to be critical for the maintenance of mature fat. Results also show that overexpression of NF-kappaB inhibits C/EBP-alpha expression, suggesting that analogous to skeletal muscle, cytokine-induced fat wasting may be mediated through the actions of NF-kappaB by targeting a key transcription factor. The main objective of this proposal is to better understand how cytokines, signaling through NF-kappaB, regulate tissue differentiation relevant in disease conditions such as cancer cachexia. This objective will be accomplished by performing the following three aims:
AIM 1 will address how cytokines TNF + IFN-gamma and NF-kappaB lead to skeletal muscle decay;
AIM 2 will investigate how TNF and NF-kappaB regulate the loss of adipocyte tissue;
and AIM 3 will determine the requirement of TNF + IFN-gamma and NF-kappaB in skeletal muscle wasting in vivo. The completion of these AIMS will provide insight on the potential of NF-kappaB as a therapeutic target in cancer cachexia.
