Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response

Abstract

Objective: Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting.

Methods: The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes.

Results: Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment.

Conclusion: Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway.

Keywords: Fbx32; JAK2/STAT3; cancer cachexia; pantoprazole; ubiquitin.

Figure 1. The average distance of the spontaneous activity of mice in different groups at different time points

**p<0.01 compared with the combination group.

Figure 2. The different expression levels of JAK/STAT3-related proteins in different groups

(A-D) The mRNA levels of JAK2 and STAT3 in the cachexia group with or without pantoprazole treatment; (E-N) the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 proteins in the cachexia group with or without pantoprazole treatment.

Figure 3. The expression levels of Fbx32 and MuRF1 proteins in different groups

The representative images and the percentage of expression levels of Fbx32 (A) and MuRF1 (B) with immunohistochemistry staining in the NC and CC groups; the representative images and the percentage of expression levels of Fbx32 (C) and MuRF1 (D) with immunohistochemistry staining in CL, CM, CH, and CS groups.