REDD1 deletion attenuates cancer cachexia in mice

Abstract

Cancer cachexia is a wasting disorder associated with advanced cancer that contributes to mortality. Cachexia is characterized by involuntary loss of body weight and muscle weakness that affects physical function. Regulated in DNA damage and development 1 (REDD1) is a stress-response protein that is transcriptionally upregulated in muscle during wasting conditions and inhibits mechanistic target of rapamycin complex 1 (mTORC1). C2C12 myotubes treated with Lewis lung carcinoma (LLC)-conditioned media increased REDD1 mRNA expression and decreased myotube diameter. To investigate the role of REDD1 in cancer cachexia, we inoculated 12-week old male wild-type or global REDD1 knockout (REDD1 KO) mice with LLC cells and euthanized 28-days later. Wild-type mice had increased skeletal muscle REDD1 expression, and REDD1 deletion prevented loss of body weight and lean tissue mass, but not fat mass. We found that REDD1 deletion attenuated loss of individual muscle weights and loss of myofiber cross sectional area. We measured markers of the Akt/mTORC1 pathway and found that, unlike wild-type mice, phosphorylation of both Akt and 4E-BP1 was maintained in the muscle of REDD1 KO mice after LLC inoculation, suggesting that loss of REDD1 is beneficial in maintaining mTORC1 activity in mice with cancer cachexia. We measured Foxo3a phosphorylation as a marker of the ubiquitin proteasome pathway and autophagy and found that REDD1 deletion prevented dephosphorylation of Foxo3a in muscles from cachectic mice. Our data provides evidence that REDD1 plays an important role in cancer cachexia through the regulation of both protein synthesis and protein degradation pathways.

Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?

“…Additionally, increased expression of REDD1 is associated with cancer cachexia through the regulation of both protein synthesis and degradation signaling. Thus, it was found that REDD1 knockout prevented Foxo3a dephosphorylation in muscles of cachectic mice [ 89 ]. Further study revealed that REDD1 expression at mRNA and protein level could be decreased by p38 mitogen-activated protein kinase (MAPK) inhibition with SB203580, which significantly suppressed p38 phosphorylation, down-regulated REDD1, and reversed autophagy in a dose-dependent manner in atrophic cells [ 90 ].…”

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

“…84–86 Table 2 summarizes the mechanism of cachexia. 13,14,34,87–124 The broad picture of CC is summarized in Figure 1.…”

“…99 Deletion of REDD1 in LLC-conditioned C2C12 myoblasts showed that elevated phosphorylation of FOXO3A, Akt1, mTORC1 prevented cachexia. 105 Furthermore, knockout of lipocalin 2 (LCN2) in pancreatic cachexia mice models showed the suppression of food intake by directly acting on CNS upon crossing the blood-brain barrier. 115 Recently, transcriptome profiling of rectus abdominis muscle from pancreatic cancer patients showed 340 differentially expressed genes, including FOXO1, FOXO3, phosphoinositide-3-kinase regulatory subunit 1 (PIK3RI), glutamate-ammonia ligase (GLUL), interleukin-6 receptor (IL-6R), ZIP14, protein phosphatase 1 regulatory subunit 8 (PPP1R8), apoptosis enhancing nuclease (AEN), coiled-coil domain containing 68 (CCDC68), Wnt family member 9A (WNT9A), protein O-mannosyl transferase 2 (POMT2), sestrin 1 (SESN1), ring finger protein 207 (RNF207), and dystonin (DST) were found to be correlated with an increasing grade of weight loss in cancer patients.…”

Impact of prior alcohol use on the subsequent development of cancer cachexia in male and female mice

“…Skeletal muscle protein balance is also perturbed during cancer cachexia by an increase in protein degradation occurring through the ubiquitin‐proteasome system, characterized by increased expression of the E3 ligases muscle RING‐finger protein‐1 (MuRF1) and Muscle Atrophy F‐box gene (MAFbx or Atrogin‐1; Penna et al, 2013; Rausch et al, 2021). Enhancement of autophagy has also been observed in both cancer and alcohol models with unc‐51 like autophagy activating kinase 1 (ULK1) phosphorylation on its mTORC1‐dependent site (Ser757) being decreased and the ratio of the lipidated to nonlipidated form of microtubule‐associated proteins 1A/1B light chain 3B (LC3) being increased (Hain et al, 2021; Thapaliya et al, 2014). Not surprisingly, the combination of continued alcohol intake and cancer cachexia leads to greater increases in markers of the ubiquitin‐proteasome system, indicating a synergistic effect of alcohol with cancer on skeletal muscle breakdown pathways (Wang et al, 2017).…”