探討S100A9與特定小分子抑制劑Tasquinimod對於胰臟癌誘發惡質症的治療效果

Abstract

惡質症（Cachexia）是一種多因素導致的消耗性代謝症候群，常見於癌症、愛滋病（HIV）、慢性阻塞性肺病（COPD）及鬱血性心衰竭（CHF）等慢性疾病患者。其主要特徵為骨骼肌的流失和全身性的發炎症狀。在癌症患者中，接近80%的癌症患者會在中後期併發惡質症，其中胰臟癌更是所有癌症中發生惡質症比例最高的一群。 實驗室過去研究發現，在胰臟癌患者中表現量顯著上調的鈣離子結合蛋白S100A9，會透過與小鼠肌肉細胞C2C12的Toll-Like Receptor 4, TLR4結合並活化IKK/NF-κB訊息路徑，從而促進會降解肌肉相關蛋白的E3-泛素連接酶，MuRF1和Atrogin-1的表達，最終造成肌肉細胞的萎縮。 Tasquinimod（TASQ）是一種口服小分子臨床藥物，作為S100A9特異性抑制劑，TASQ可以抑制S100A9與TLR4之間相互作用。我們透過對C2C12細胞進行S100A9和TASQ聯合處理的，發現TASQ有效抑制S100A9透過TLR4或經由訊息路徑，減少MuRF1和Atrogin-1的轉錄，進而緩解肌肉細胞的萎縮。為了進一步研究S100A9與TASQ之間的交互作用，我們透過分子對接與分子動力學模擬，發現TASQ會透過和S100A9中Helix III與Helix IV上的特定胺基酸形成氫鍵與疏水性作用，來與S100A9結合。 我們的研究結果表明，S100A9可以透過和小鼠肌肉細胞的TLR4結合，活化下游Myd88/IKK/NF-κB調控的訊息通路，誘導肌肉相關蛋白降解，造成肌肉細胞的萎縮。TASQ可以透過和S100A9結合，抑制S100A9造成的肌肉相關蛋白降解。透過探討S100A9與惡質症之間的機制，以及Tasquinimod的效果，對於未來針對胰臟癌致惡質症的治療策略提供了新的方向。

Cachexia is a multifactorial wasting syndrome commonly observed in patients with chronic diseases such as cancer, HIV, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF). It is primarily characterized by skeletal muscle loss and systemic inflammation. In cancer patients, nearly 80% develop cachexia in the later stages of the disease, with pancreatic cancer having the highest incidence of cachexia among all cancer types. Previous studies in our laboratory have identified the calcium-binding protein S100A9, which is significantly upregulated in pancreatic cancer patients. S100A9 interacts with Toll-Like Receptor 4 (TLR4) on mouse muscle cells (C2C12), activating the IKK/NF-κB signaling pathway. This activation promotes the expression of muscle-degrading E3 ubiquitin ligases, MuRF1 and Atrogin-1, leading to muscle cell atrophy. Tasquinimod (TASQ) is an oral small-molecule clinical drug that acts as a specific inhibitor of S100A9. TASQ can inhibit the interaction between S100A9 and TLR4. Our studies, involving co-treatment of C2C12 cells with S100A9 and TASQ, demonstrated that TASQ effectively inhibits S100A9-mediated signaling through the TLR4 pathway, reducing the transcription of MuRF1 and Atrogin-1 and consequently alleviating muscle cell atrophy. Further molecular docking and molecular dynamics simulations revealed that TASQ binds to S100A9 through the formation of hydrogen bonds and hydrophobic interactions with specific amino acids on Helix III and Helix IV of S100A9. Our findings indicate that S100A9 can bind to TLR4 on mouse muscle cells, activating the MyD88/IKK/NF-κB-regulated signaling pathway, inducing muscle protein degradation and resulting in muscle cell atrophy. TASQ, by binding to S100A9, can inhibit the muscle protein degradation caused by S100A9. Investigating the mechanisms between S100A9 and cachexia, as well as the effects of Tasquinimod, provides new insights for future therapeutic strategies against pancreatic cancer-induced cachexia.