Lung Cancer-associated cachexia: the relationship between Parkin and mTOR pathways in the tumor and in skeletal muscle

• Grant number: 23/04275-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2023
• Status: Discontinued
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Marcos Vinicius Esteca
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 24/20032-9 - Targeting the mTOR pathway through senotherapeutics to restore musculoskeletal health in cancer survivors, BE.EP.PD

Abstract

Cancer is a disease with a high global prevalence, being a primary topic for investment instudies. Recently there have been advances in the understanding of the mechanisms, but there is still a lack of efficient treatments and ways to improve the survival of patients with current treatments. Among the types of cancer, lung cancer is one of the most prevalent in the world and the one thatcauses the most deaths. A factor that is commonly associated with cancer is cachexia, which is acondition with a large loss of skeletal muscle, reducing the quality of life and chances of survival after treatment with curative intent. Parkin has already been studied in several types of cancer as a tumor suppressor, but there is some evidence that points to a contradictory effect in lung cancer. mTOR is a central kinase in the synthesis pathways that maintain tumor growth and, in skeletal muscle, the drop in its activity is one of the factors that generate cachexia. There is some evidence that shows that Parkin and mTOR may form a regulatory axis of growth pathways byphosphorylation and ubiquitination in the context of oxidative stress or cancer. In this context, weaim to investigate the relationship between Parkin E3 ligase and mTOR in lung cancer and inskeletal muscle in cancer-associated cachexia. To investigate this relationship further in cancer, we aimed to implement a KP mouse lung cancer model (LSL-Kras12G p53flox/flox) with the knockout toParkin on cancer. In the skeletal muscle, we will overexpress Parkin in the KP lineage through thetransduction of AAV to Parkin and use several experimental approaches to investigate the effect on the maintenance of muscle mass in the context of lung cancer. Additionally, we will use AAVs forS6Ks in skeletal muscle and explore the effects of overexpression of these proteins to advanceknowledge about the mechanisms that link mitochondrial metabolism, autophagy, and proteinsynthesis. This project should contribute to a better understanding of Parkin's role in cancer and the molecular pathways associated with the development of cancer-associated cachexia. (AU)