Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

Abstract

Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3b were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia.

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

“…In our study, we observed that PDTC slightly inhibited the phosphorylation of p65 enhanced by C26 medium, suggesting other signaling pathways were employed by PDTC to relieve cancer cachexia. It is reported that the phosphorylation of AKT was inhibited in muscle atrophy ( Quan-Jun et al, 2017 ), and the reduction of AKT phosphorylation led to increased MuRF1 transcription ( Wadosky et al, 2014 ), so we wondered whether PDTC would affect the activation of AKT. Meaningfully, PDTC effectively increased the phosphorylation of AKT in C26 medium-treated C2C12 myotubes.…”

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

“…Biliary, colon and lung cancers might exert muscle wasting through different effectors. In the C26 studies, ERK inhibition had no effect on tumor mass in one study (Penna et al, 2010), but resulted in an ~15% decrease in tumor mass in another study (Quan-Jun et al, 2016). However, the studies each used different inhibitors and the mice from both were of a different genetic background than those used here.…”

“…Pharmacological inhibition of ERK1/2 significantly increases mRNA levels of the transcription factor myogenin, promoting differentiation and expression of muscle specific genes and the myogenic program (Adi et al, 2002). Finally, ERK inhibition has also been shown to prevent muscle wasting in a C26 colon carcinoma mouse model of cancer cachexia (Penna et al, 2010; Quan-Jun et al, 2016). …”

Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia

“…This condition occurs in nearly 80% of patients with advanced cancer and contributes to approximately 30% of cancer mortality . It is associated with a reduced quality of life, reduced therapy response, and reduced treatment tolerance . Recent clinical and experimental evidence clearly indicates that cancer cachexia is not an ineluctable occurrence, and an international consensus on the definition of cancer cachexia has been reached .…”

“…5 It is associated with a reduced quality of life, reduced therapy response, and reduced treatment tolerance. 2,6 Recent clinical and experimental evidence clearly indicates that cancer cachexia is not an ineluctable occurrence, 1,[7][8][9] and an international consensus on the definition of cancer cachexia has been reached. 10 However, there is no molecular biomarker with high sensitivity and specificity that can be employed for the early and accurate diagnosis of cancer cachexia.…”