PO.MCB03.02 · 分子与细胞生物学
beta,beta-二甲基丙烯酰紫草素通过靶向FGFR1在体外和体内抑制结直肠癌生长
beta , beta -dimethylacrylalkannin inhibits colorectal cancer growth in vitro and in vivo by targeted FGFR1
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：结直肠癌（CRC）仍是全球一项重大的健康挑战，位居癌症相关死亡的首要原因之列。令人担忧的是，CRC患者的五年生存率仅徘徊在10-30%左右。成纤维细胞生长因子受体（FGFR）信号通路的紊乱与结直肠癌（CRC）的发生和进展密切相关，为CRC治疗干预提供了一个有前景的靶点。进一步的研究对于全面阐明FGFR1在CRC中的作用以及开发有效的FGFR1靶向治疗至关重要。
目的：本研究旨在阐明FGFR1在结直肠癌中的致癌作用，并利用beta,beta-二甲基丙烯酰紫草素（beta,beta-DMAA）作为FGFR1抑制剂，研究抑制FGFR1活性的潜在治疗益处。
方法：在本研究中，我们进行了组织芯片、激酶谱分析实验、计算对接模型、敲低实验，以预测和探索FGFR1的抑制剂。此外，我们利用激酶实验、pull-down、细胞增殖和患者来源异种移植（PDX）小鼠模型实验，以发现一种FGFR1抑制剂并评估其对结直肠癌生长的影响。
结果：在本研究中，我们发现FGFR1蛋白在结直肠癌中显著过表达，并在调控细胞生长中起关键作用，尤其是在结直肠癌患者中。此外，我们进行了计算对接、激酶谱分析和模拟，识别出beta,beta-DMAA能够在ATP结合口袋结构域内直接与FGFR1结合。基于细胞的实验证实，beta,beta-DMAA不仅抑制结肠癌细胞的生长，还诱导细胞周期阻滞、凋亡以及FGFR1介导信号通路的调节。此外，beta,beta-DMAA有效减弱了FGFR1阳性小鼠中PDX肿瘤的生长，且未造成明显毒性。总之，我们的研究突显了FGFR1在结直肠癌中的关键作用，提示抑制FGFR1活性可能是一种有前景的治疗干预策略。我们提供了有力证据表明，用beta,beta-DMAA靶向FGFR1是结直肠癌治疗管理的一种可行方法。鉴于其低毒性和高疗效，beta,beta-DMAA作为一种FGFR1抑制剂，值得在临床环境中进一步研究，用于治疗FGFR1阳性肿瘤。
查看英文原文 English abstract
Background: Colorectal cancer (CRC) continues to be a major global heaith challenge, ranking as a top cause of cancer-related death fatalities. Alarmingly, the five-year survival rate for CRC patients hovers around a mere 10-30%. The disruption of fibroblast growth factor receptor (FGFRs) signaling pathways is significantly implicated in the onset and advancement of colorectal cancer (CRC), presenting a promising target for therapeutic intervention in CRC management. Further investigation is essential to comprehensively elucidate the role of FGFR1 in CRC and to develop effective FGFR1-targeted therapies.
Purpose: This study aims to demonstrate the oncogenic role of FGFR1 in colorectal cancer and investigate the potential therapeutic benefits of inhibiting FGFR1 activity using beta , beta -dimethylacrylalkannin ( beta , beta -DMAA) as an FGFR1 inhibitor.
Methods: In the present study, we performed tissue array, kinase profiling analysis assay, computational docking model, knockdown assay to predict and explore the inhibitor of FGFR1. Furthermore, we utilized kinase assay, pull-down, cell proliferation and Patient derived xenograft (PDX) mouse model assays to discover an FGFR1 inhibitor and assess its effects on colorectal cancer growth.
Results: In this study, we found that FGFR1 protein is significantly overexpressed in colorectal cancer and plays a pivotal role in regulated cell growth, particularly in colorectal cancer patients. Furthermore, we conducted a computational docking, kinase profiling analysis, simulation and identified that beta , beta -DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that beta , beta -DMAA not only inhibited the growth of colon cancer cells but also induced cell cycle arrest, apoptosis, and the modulation of FGFR1-mediated signaling pathways. Moreover, beta , beta -DMAA effectively attenuated the growth of PDX tumors in mice that were FGFR1-positive, all without causing significant toxicity. In summary, our study highlights the pivotal role of FGFR1 in colorectal cancer, suggesting that inhibiting FGFR1 activity could be a promising strategy for therapeutic intervention. We present strong evidence that targeting FGFR1 with beta , beta -DMAA is a viable approach for the management of colorectal cancer. Given its low toxicity and high efficacy, beta , beta -DMAA, as an FGFR1 inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors.
利益披露 Disclosure
R. Zhao, None..
F. Yin, None.