Abstract
Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin resistance, dysfunctional mitochondria, oxidative stress, and heightened activation of ubiquitin-proteasome system and macroautophagy. Accumulating evidence suggests that deviant regulation of an array of signaling pathways engenders cancer cachexia where the human body is sustained in an incessant self-consuming catabolic state. Recent studies have further suggested that several components of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle of animal models and muscle biopsies of cachectic cancer patients. However, the exact role of ER stress and the individual arms of the UPR in the regulation of skeletal muscle mass in various catabolic states including cancer has just begun to be elucidated. This review provides a succinct overview of emerging roles of ER stress and the UPR in cancer-induced skeletal muscle wasting.
Highlights
Cachexia is a multifactorial syndrome characterized by progressive loss of skeletal muscle mass and functional impairment
Consistent with our findings with Lewis lung carcinoma (LLC) tumor-bearing mice, another study recently demonstrated that genetic ablation of myeloid differentiation primary response gene 88 (MyD88) attenuates muscle wasting and improves survival in a mouse model of pancreatic cancer cachexia further suggesting that the toll-like receptor (TLR)/MyD88 signaling axis mediates the loss of skeletal muscle mass during cancer cachexia [35]
We have recently reported that TLRs regulate the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring protein 1α (IRE1α) arms of the unfolded protein response (UPR) in skeletal muscle of LLC
Summary
Cachexia is a multifactorial syndrome characterized by progressive loss of skeletal muscle mass and functional impairment. Consistent with our findings with LLC tumor-bearing mice, another study recently demonstrated that genetic ablation of MyD88 attenuates muscle wasting and improves survival in a mouse model of pancreatic cancer cachexia further suggesting that the TLR/MyD88 signaling axis mediates the loss of skeletal muscle mass during cancer cachexia [35]. 4-PBA inhibits the rate of protein synthesis and Akt/mTOR pathway and augments the activation of proteolytic systems during cancer cachexia [51] suggesting that some level of ER stress may be essential for maintaining skeletal muscle mass and health even in naïve conditions. As ER stress response effectuates through the independent activation of IRE1, PERK, and ATF6 pathways along with added signaling regulation and crosstalk, it is imperative to understand the role of individual arm of the UPR in distinct models of cancer cachexia
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