Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase

Abstract

Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid’s effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids.

Implication of Ceramide Kinase/C1P in Cancer Development and Progression

“…Of interest, other molecular processes have been similarly involved in these phenotypes, including the C1P-mediated vascular endothelial growth factor (VEGF) production in macrophages [22] or C1P-induced lysophosphatidic acid (LPA) receptor activation in myoblasts [23]. In line with the latter report, Meacci and co-workers have recently shown that the CERK/C1P axis plays a crucial role as molecular regulator of skeletal muscle mass associated with cancer [24]. In addition to stimulating cell proliferation, C1P can increase cell number through the inhibition of apoptosis.…”

Silibinin Alleviates Muscle Atrophy Caused by Oxidative Stress Induced by Cisplatin through ERK/FoxO and JNK/FoxO Pathways

“…The activation of protein degradation-related pathways is the cause of muscle atrophy in cachexia. Skeletal muscle degradation is usually accompanied by the activation of the ubiquitin system, upregulation of MAFbx, and downregulation of MyHC expression in muscle-specific E-3 ubiquitin ligase [ 16 ]. The expression of active caspase3 in mice was upregulated after cisplatin, indicating the occurrence of muscle apoptosis, which could be improved by SLI treatment ( Figure 4(a) ).…”

What Role Do Inflammatory Cytokines Play in Cancer Cachexia?

“…MAPK pathway additionally inhibits the proliferation and differentiation of myocytes. CCAAT/enhancer-binding proteins-6 beta (C/EBPb) is a major regulator of myoblast and is activated by IL-6 and IL-1, resulting in myogenesis inhibition and muscle fiber size reduction [ 8 , 26 ].…”

“…GDF-15 is another cytokine belonging to the TGF-beta family which is increased in cancer cachexia and is responsible for the regulation of lean body mass and body weight [ 15 ]. TNF-α also decreases the ceramide kinase reducing the conversion of ceramide to ceramide-1-phosphate leading to ceramide accumulation and resulting in myotube atrophy [ 26 ]. In addition to these effects, IL-6 brings about changes in redox balance in muscle tissue by inhibiting the anti-oxidant work and increasing the fast fibers in muscle which are more prone to atrophy [ 27 ].…”