Pre-cachectic changes in amino acid homeostasis precede activation of eIF2α signaling in the liver at the onset of C26 cancer-induced cachexia.

The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.