Alterations in Hepatic Protein Synthetic Signaling During the Progression of Cancer Cachexia
Authors: Rosa‐Caldwell Megan , Brown Jacob L. , Lee David E. , Perry Richard A. , Haynie Wesley A. , Caldwell Aaron R. , Washington Tyrone A. , Wiggs Michael P. , Greene Nicholas P. 
Published: June 2021

Cancer and its associated co‐morbidities remain a significant public health concern. Specifically, cancer‐associated muscle wasting (cancer cachexia) is a strong predictor of cancer‐associated mortality. Cachexia is thought to be partially mediated by increased energy expenditure, as the liver is the predominant regulator of whole body energy expenditure, it is plausible that alterations in liver physiology may contribute to cachexia. More so, liver hypertrophy is a common pathological hepatic manifestation of cachexia, which has been demonstrated to directly relate to energy expenditure. Therefore, understanding the mechanisms underlying hepatic hypertrophy is critical for understanding hepatic pathologies of cachexia.

Purpose

To examine alterations in hepatic protein synthetic pathways during the progression of cancer cachexia.

Methods

C57BL/6J mice were injected with either phosphate buffered saline (CON) or 1×106 Lewis Lung Carcinoma (LLC) cells in the hind flank. Cancer progressed for 1, 2, 3, or 4 weeks, mice were then humanely euthanized, and livers collected for analysis (n=10–16/group). CON animals were age‐matched with 4 week animals. Subsets of each group (n=8/group) were analyzed by Western blot for measures of hepatic protein synthesis. Data were analyzed by oneway ANOVA with independent factors of cancer progression (CON, 1, 2, 3, or 4 weeks). When significant F‐ratios were found, a Dunnett's post hoc was used to compare differences between experimental groups and control. Significance was denoted at p<0.05.

Results

Livers from 4 week animals were 30% larger compared to CON with no other differences noted compared to CON (p<0.05). Total Akt protein content was ~8.5‐fold greater in 4 week animals compared to control (p<0.05). p‐AktSer473 was ~3.5‐fold greater in 4 week animals compared to control. However, p‐Akt Ser473/Akt ratio demonstrated a ~35–45% decrease in 1 week, 2 week, 3 week, and 4 week animals compared to control. There were no differences in total p70, p‐p70Thr389, or p‐p70Thr389/p70 content between groups. Total 4EBP1 was not different between groups, however, an apparent ~1.7‐fold greater p‐4EBP1Thr37/46 appeared in 4 week animals, approached statistical significance (p=0.08). There were no statistical differences on p‐4EBP1Thr37/46/4EBP1 ratio.

Conclusions

Cancer progression causes marked alterations in upstream signaling in hepatic protein synthesis, however these differences may not necessarily translate to alterations in downstream hepatic protein synthesis signaling. More research is necessary to identify the precise mechanisms of hepatic hypertrophy in the progression of cancer cachexia.

Support or Funding Information

This study was supported by The Arkansas Bioscience Institute and National Institutes of Health R15AR069913.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.