Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways

Qiao-Yu Fang; Yue-Ping Wang; Rui-Qin Zhang; Meng Fan; Li-Xing Feng; Xiao-Dong Guo; Chun-Ru Cheng; Xiong-Wen Zhang; Xuan Liu

doi:10.3389/fphar.2023.1291194

Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways

Front Pharmacol. 2024 Jan 5:14:1291194. doi: 10.3389/fphar.2023.1291194. eCollection 2023.

Authors

Qiao-Yu Fang¹, Yue-Ping Wang¹, Rui-Qin Zhang¹, Meng Fan², Li-Xing Feng³, Xiao-Dong Guo⁴, Chun-Ru Cheng⁵, Xiong-Wen Zhang², Xuan Liu¹

Affiliations

¹ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
³ Shanghai Majorbio Bio-Pharm Technology Co., Ltd., Shanghai, China.
⁴ Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ School of Chemical Engineering, Sichuan University of Science and Engineering, Zigong, Sichuan, China.

Abstract

Introduction: Carnosol exhibited ameliorating effects on muscle atrophy of mice developed cancer cachexia in our previous research. Method: Here, the ameliorating effects of carnosol on the C2C12 myotube atrophy result from simulated cancer cachexia injury, the conditioned medium of the C26 tumor cells or the LLC tumor cells, were observed. To clarify the mechanisms of carnosol, the possible direct target proteins of carnosol were searched using DARTS (drug affinity responsive target stability) assay and then confirmed using CETSA (cellular thermal shift assay). Furthermore, proteomic analysis was used to search its possible indirect target proteins by comparing the protein expression profiles of C2C12 myotubes under treatment of C26 medium, with or without the presence of carnosol. The signal network between the direct and indirect target proteins of carnosol was then constructed. Results: Our results showed that, Delta-1-pyrroline-5-carboxylate synthase (P5CS) might be the direct target protein of carnosol in myotubes. The influence of carnosol on amino acid metabolism downstream of P5CS was confirmed. Carnosol could upregulate the expression of proteins related to glutathione metabolism, anti-oxidant system, and heat shock response. Knockdown of P5CS could also ameliorate myotube atrophy and further enhance the ameliorating effects of carnosol. Discussion: These results suggested that carnosol might ameliorate cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways.

Keywords: P5CS; aldehyde dehydrogenase family 18 member A; cancer cachexia; carnosol; myotube atrophy; proteomics; target protein.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Nature Science Foundation of China (Nos 82374085, 82373317, 22377087, and 82303818); the Natural Science Foundation of Shanghai (Nos 23ZR1460500 and 21ZR1464400).