ER Stress and Unfolded Protein Response in Cancer Cachexia

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.

Keywords: ATF4; ATF6; ER stress; IRE1; PERK; Skeletal muscle; XBP1; and signaling.; cancer cachexia.

Figure 1

Major pathways involved in muscle loss in cancer cachexia. The ubiquitin-proteasome system and autophagy are the major modes of proteolysis in cancer cachexia. Native proteins destined to non-lysosomal degradation are polyubiquitylated by E3 ubiquitin ligases like MuRF1, MAFbx, and MUSA before being fragmented into smaller peptides by the 26S proteasome. Autophagy removes defunct organelles and protein aggregates by assembling them into phagophores followed by autophagosome formation. Autolysosomes are then formed by fusion of autophagosomes with lysosomes, which degrade the engulfed components. Growth stimulating ligand binds to receptor tyrosine kinases to phosphorylate and activate Akt, which consequently triggers mammalian target of rapamycin (mTOR) pathway to increase rate of protein synthesis and decrease protein degradation. SMAD2 and the energy sensor kinase AMPK can also regulate cellular protein level by inhibiting Akt and mTOR, respectively. Phosphorylated Akt also prevent the nuclear localization of FOXO proteins by phosphorylating them, however, in cachexia, pAkt is inhibited resulting in mTOR pathway suppression and nuclear translocation of FOXO proteins. FOXO proteins in nucleus trigger transcription of genes encoding proteins for autophagy mechanism and atrogenes like MAFbx, MuRF1, and MUSA. Transcription of these genes are also promoted by NF-κB and p38 MAPK activated by pro-inflammatory cytokines, Toll-like receptor/MyD88, Activin/Activin receptor axis.

Figure 2

Putative mechanisms of action of unfolded protein response (UPR) in cancer cachexia. Misfolded proteins accumulated in the endoplasmic reticulum (ER) lumen bind to glucose-regulated protein 78 (GRP78) resulting in its dissociation from intraluminal domains of ER stress sensors protein kinase R-like endoplasmic reticulum kinase (PERK), IRE1α, and activating transcription factor 6 (ATF6) to consequently trigger their activation. PERK undergoes dimerization and trans-autophosphorylation before phosphorylating and activating eIF2α. Under conditions when PERK is hyper-activated, p-eIF2α inhibits protein synthesis and activates activating transcription factor 4 (ATF4). ATF4 up-regulates C/EBP homologous protein (CHOP) expression which is responsible for inducing autophagy machinery genes. Complete deletion of PERK gene also induces the expression of atrogenes, autophagy promoting genes and calpains. The endonuclease domain of activated IRE1α splices the unspliced XBP1 (uXBP1) to spliced form (sXBP1). sXBP1 escalates the gene expression of atrogenes and autophagy-related molecules to effectuate cachexia. The ER sensor ATF6 is translocated to Golgi following its activation where it is sequentially cleaved by site1 protease (S1P) and site2 protease (S2P) proteases. The cleaved fragment ATF6f promotes cachexia by mediating insulin resistance in skeletal muscle.