Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia

by Selleckchem | Dec 11 2023

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

Comments:

The provided passage describes a study focused on cancer cachexia, a condition characterized by muscle and fat tissue wasting due to systemic inflammation. The researchers investigated the role of extracellular vesicles (EVs) derived from Lewis lung carcinoma (LLC) cells in promoting lipolysis (breakdown of fat) in adipocytes, contributing to the weight loss observed in cancer cachexia. Here are the key points from the study:

1. **Background:** Cancer cachexia is a condition marked by muscle and fat tissue wasting, leading to severe weight loss and physiological impairment. The underlying mechanism involves systemic inflammation.

2. **Role of EVs:** EVs derived from LLC cells were isolated and studied. These EVs were found to induce lipolysis in 3T3-L1 and HIB1B adipocytes when cultured with them. Additionally, these EVs were used to establish a cancer cachexia mouse model.

3. **Identification of EIF5A:** The researchers identified a protein called EIF5A in the EVs, which was found to be associated with lipid metabolism. Elevated levels of EIF5A were linked to shorter overall survival in lung cancer patients.

4. **Mechanism of Lipolysis:** EIF5A, present in the EVs, directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA, promoting its translation. This, in turn, activates the cAMP response element-binding protein (CREB) signaling pathway, leading to lipolysis in adipocytes.

5. **Interventions:** In vitro experiments involved silencing EIF5A or using a pharmacologic inhibitor called GC7, leading to reduced lipolysis in 3T3-L1 and HIB1B adipocytes. Similarly, in vivo experiments involved suppressing EIF5A expression in LLC cells using shRNA or GC7 treatment, which partially alleviated lipolysis in white and brown adipose tissues.

6. **Implications:** Exosomal EIF5A from LLC cells, specifically hypusinated EIF5A, was identified as a key factor inducing lipolysis in adipocytes and adipose tissues in the context of cancer cachexia. The findings suggest that exosomal EIF5A could be a potential target for the treatment of cachexia.

In summary, this study provides insights into the molecular mechanisms behind cancer cachexia, specifically focusing on the role of EVs and the protein EIF5A in promoting adipocyte lipolysis. Targeting exosomal EIF5A might hold promise as a potential therapeutic strategy for cachexia associated with cancer.