Endoplasmic Reticulum Stress, Calcium Dysregulation and Altered Protein Translation: Intersection of Processes That Contribute to Cancer Cachexia Induced Skeletal Muscle Wasting

Title:Endoplasmic Reticulum Stress, Calcium Dysregulation and Altered Protein Translation: Intersection of Processes That Contribute to Cancer Cachexia Induced Skeletal Muscle Wasting

Volume: 17 Issue: 10

Author(s): Stephanie T. Isaac, Timothy C. Tan and Patsie Polly

Affiliation:

Keywords: Skeletal muscle, cancer cachexia, endoplasmic reticulum, protein translation, calcium, cytokines.

Abstract: 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.

Cite this article as:

Isaac T. Stephanie, Tan C. Timothy and Polly Patsie, Endoplasmic Reticulum Stress, Calcium Dysregulation and Altered Protein Translation: Intersection of Processes That Contribute to Cancer Cachexia Induced Skeletal Muscle Wasting, Current Drug Targets 2016; 17 (10) . https://dx.doi.org/10.2174/1389450116666150416115721