Corylifol A ameliorates pancreatic cancer-associated cachexia by targeting TAOK3 in pancreatic cancer cells and targeting TAOK1 in skeletal muscle cells

As many as 80 % of pancreatic cancer patients might suffer from cancer cachexia, a distressing condition characterized by involuntary weight loss and muscle wasting. Regrettably, there remains an insufficiency of efficacious pharmacological interventions for the management of cancer cachexia. The effectiveness of corylifol A (CYA) in treating pancreatic cancer-associated cachexia was assessed, and its underlying mechanisms were examined in the present study. Cultured C2C12 myotubes induced with conditioned medium from MiaPaCa-2 pancreatic cancer cells (MIA CM) were utilized as an in vitro model to investigate the impact of CYA on muscle atrophy associated with cancer cachexia. The MIA cachexia mice model was utilized to evaluate the in vivo impact of CYA on cancer cachexia. CYA (2.5, 5, and 10 μM) dose-dependently mitigated MIA CM-induced myotube atrophy through targeting the thousand and one amino acid protein kinase 1 (TAOK1) and blocking protein degradation via the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP). Importantly, CYA (10 mg/kg/d, i.p.) not only significantly ameliorated weight loss and muscle atrophy but also inhibited the tumor growth in MIA cancer cachexia mice. In pancreatic cancer cells, CYA directly targets the thousand and one amino acid kinase 3 (TAOK3). Both knockdown and overexpression of TAOK3 could alleviate the cytotoxicity of CYA on pancreatic cancer cells. Collectively, CYA ameliorated pancreatic cancer-associated cachexia by targeting TAOK1 in skeletal muscle cells as well as targeting TAOK3 in pancreatic cancer cells.