Cancer cachexia is a debilitating paraneoplastic wasting syndrome characterized by skeletal
muscle depletion and unintentional weight loss. It affects up to 50-80% of patients with cancer and directly
accounts for one-quarter of cancer-related deaths due to cardio-respiratory failure. Muscle
weakness, one of the hallmarks of this syndrome, has been postulated to be due to a combination of
muscle breakdown, dysfunction and decrease in the ability to repair, with effective treatment strategies presently limited.
Excessive inflammatory cytokine levels due to the host-tumor interaction, such as Interleukin (IL)-6 and Tumor Necrosis
Factor (TNF)-α, are hypothesised to drive this pathological process but the specific mechanisms by which these cytokines
produce skeletal muscle dysfunction in cancer cachexia remain undefined. Endoplasmic Reticulum (ER) stress and the associated
disruptions in calcium signaling have been implicated in cytokine-mediated disruptions in skeletal muscle and
function. Disrupted ER stress-related processes such as the Unfolded Protein Response (UPR), calcium homeostasis and
altered muscle protein synthesis have been reported in clinical and experimental cachexia and other inflammation-driven
muscle diseases such as myositis, potentially suggesting a link between increased IL-6 and TNF-α and ER stress in skeletal
muscle cells. As the concept of upregulated ER stress in skeletal muscle cells due to elevated cytokines is novel and
potentially very relevant to our understanding of cancer cachexia, this review aims to examine the potential relationship
between inflammatory cytokine mediated muscle breakdown and ER stress, in the context of cancer cachexia, and to discuss
the molecular signaling pathways underpinning this pathology.
Keywords: Skeletal muscle, cancer cachexia, endoplasmic reticulum, protein translation, calcium, cytokines.
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