Swain Abinash, Mahapatra Pinaki Prasad, Nirwan Abhishek, Gupta Neelam, Kumar Arun, Saxena Rashi, Kaur Jaspreet, Ahmed Shakil, Mishra Durga Prasad
Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension Lucknow, Uttar Pradesh 226031, India.
Molecular and Structural Biology Division, Central Drug Research Institute (CSIR), Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative research (AcSIR), Ghaziabad 201002, India.
Biomed Pharmacother. 2025 Nov;192:118561. doi: 10.1016/j.biopha.2025.118561. Epub 2025 Sep 18.
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.
以显著肌肉萎缩和肌肉丢失为特征的癌症恶病质是结直肠癌相关发病率和死亡率的一个决定性标志。尽管治疗取得了进展，但目前的治疗策略常常受到全身毒性、心血管并发症和低反应率等副作用的限制，因此需要替代方法来管理结直肠癌恶病质。已知聚（ADP - 核糖）聚合酶1（PARP1）可调节氧化应激以及肌肉中的蛋白质分解代谢。然而，PARP1在肌肉萎缩调节中的作用仍知之甚少，有待充分阐明。PARP抑制剂奥拉帕尼已在多种癌症模型中显示出抗癌作用；然而，其对结直肠癌恶病质的影响尚不清楚。因此，在本研究中，我们使用奥拉帕尼研究了PARP1在调节结直肠癌恶病质中的作用及其潜在分子机制。用奥拉帕尼对PARP1进行药理学抑制可逆转结直肠癌恶病质体外和体内模型中的肌肉萎缩参数。此外，我们发现转录因子RUNX3在结直肠癌恶病质中通过PARP1介导的PARylation调节与肌肉萎缩相关的E3泛素连接酶MuRF1的表达。此外，RUNX3与MuRF1启动子的结合导致结直肠癌恶病质中MuRF1转录的激活。总之，本研究首次证明了RUNX3 PARylation在调节结直肠癌恶病质肌肉萎缩中的关键作用。这些发现表明，RUNX3/PARP1信号通路有望为设计结直肠癌恶病质管理的新策略提供依据。
