Targeting RUNX3/PARP1 signaling ameliorates colorectal cancer cachexia

Cancer cachexia characterized by significant muscle atrophy and muscle loss is a defining hallmark of colorectal cancer associated morbidity and mortality. Despite advances in treatment, current therapeutic strategies are often limited by their side effects like systemic toxicity, cardiovascular complications and low response rates, necessitating alternatives for colorectal cancer cachexia management. The Poly (ADP-ribose) polymerases 1 (PARP1) is known to regulate oxidative stress, and protein catabolism in the muscle. However, the role of PARP1 in the regulation of muscle atrophy remains poorly understood and is yet to be fully elucidated. The PARP inhibitor Olaparib has demonstrated anticancer effects in multiple cancer models; however, its effects on colorectal cancer cachexia remains unknown. Therefore, in the current study we investigated the role of PARP1 in regulation of colorectal cancer cachexia using Olaparib and its underlying molecular mechanisms. Pharmacological inhibition of PARP1 with Olaparib reversed the muscle atrophy parameters both in the in vitro and in vivo models of colorectal cancer cachexia. Further, we identified that the transcription factor RUNX3 regulated the muscle atrophy associated E3 ubiquitin ligase MuRF1 expression through PARP1 mediated PARylation in colorectal cancer cachexia. Additionally, the MuRF1 promotor engagement by RUNX3 led to the activation of MuRF1 transcription in colorectal cancer cachexia. In conclusion, the current study is the first to demonstrate the critical role of RUNX3 PARylation in regulation of muscle atrophy in colorectal cancer cachexia. These findings suggest that the RUNX3/PARP1 signalling holds promise for devising novel strategies for colorectal cancer cachexia management.