The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia.

Background: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice. Methods: Adult C57BL/6J mice received orthotopic PDAC cell ( Results: 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) liberated less triglyceride into the culture media than control-treated adipocytes (-28.1%) and had lower expression of lipolysis and lipogenesis genes than control cells. PDAC gWAT cultured Conclusions: Our work highlights deficient adipose anabolism as a driver of lipid-droplet loss in 3T3-L1 adipocytes treated with PDAC conditioned media and PDAC mice. The small molecule KH-3, which disrupts HuR binding, restored adipose anabolism in PDAC mice. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.