FBXO11通过稳定TMBIM6促进结直肠癌进展：松果菊苷作为一种天然抑制剂
FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.
摘要(中文译文)
FBXO11是一种E3泛素连接酶，已被认为在多种癌症类型中具有潜在致癌驱动作用；然而，其在结直肠癌（CRC）中的生物学功能及治疗意义仍不明确。通过分析TCGA和TNMplot数据库评估FBXO11在CRC中的表达及预后意义。免疫组织化学在100例临床CRC标本中验证了相关发现。在体外（增殖、集落形成、迁移、侵袭）和体内实验中检测了FBXO11敲低的功能影响。基于结构的虚拟筛选鉴定出松果菊苷（ECH）作为FBXO11抑制剂，其结合通过CETSA和DARTS实验得到确认。包括体外pull-down和定点诱变在内的机制研究探究了FBXO11-TMBIM6相互作用及泛素化级联反应。FBXO11在CRC组织中显著上调并与不良预后相关。抑制FBXO11可在体外和体内抑制CRC恶性行为。ECH结合FBXO11并触发其经泛素-蛋白酶体途径降解，以依赖FBXO11抑制的方式抑制CRC进展，在异种移植瘤中减少肿瘤负荷且无全身毒性。在机制上，体外实验证实FBXO11与TMBIM6存在直接相互作用。ECH或FBXO11敲低破坏了该轴，损害了TMBIM6特定位点K15的K63连接泛素化，随后使其暴露于K48连接泛素化及TMBIM6的蛋白酶体降解。FBXO11通过稳定TMBIM6成为CRC进展的关键调控因子，并突显ECH作为靶向FBXO11-TMBIM6轴的有前景的治疗性降解剂。
Abstract
FBXO11, an E3 ubiquitin ligase, has been implicated as a potential oncogenic driver in multiple cancer types; however, its biological function and therapeutic significance in colorectal cancer (CRC) remain poorly defined. TCGA and TNMplot databases were analyzed to assess FBXO11 expression and prognostic significance in CRC. Immunohistochemistry validated findings in 100 clinical CRC specimens. Functional impacts of FBXO11 knockdown were tested in vitro (proliferation, colony formation, migration, invasion) and in vivo. Structure-based virtual screening identified Echinacoside (ECH) as an FBXO11 inhibitor, with binding confirmed by CETSA and DARTS assays. Mechanistic studies, including in vitro pull-down and site-directed mutagenesis, interrogated FBXO11-TMBIM6 interactions and ubiquitination cascades. FBXO11 was significantly upregulated in CRC tissues and correlated with poor prognosis. Its suppression inhibited CRC malignant behaviors in vitro and in vivo. ECH bound FBXO11 and triggered its ubiquitin-proteasomal degradation, suppressing CRC progression dependent on FBXO11 inhibition, reducing tumor burden in xenografts without systemic toxicity. Mechanistically, in vitro assays confirmed a direct FBXO11-TMBIM6 interaction. ECH or FBXO11 knockdown disrupted this axis, impairing K63-linked ubiquitination specifically at the K15 residue of TMBIM6, which subsequently unshielded it for K48-linked ubiquitination and proteasomal degradation of TMBIM6. FBXO11 is a critical regulator of CRC progression via stabilization of TMBIM6 and highlights ECH as a promising therapeutic degrader targeting the FBXO11-TMBIM6 axis.
如何引用
AMA
Chenghai He, Jingli Xu, Yuanzhen Bai, Meilin Yu, Kexin Chen, Yu Zhao, et al. FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158271.
APA
Chenghai He, Jingli Xu, Yuanzhen Bai, Meilin Yu, Kexin Chen, Yu Zhao, et al (2026). FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158271
GB/T 7714
Chenghai He, Jingli Xu, Yuanzhen Bai, Meilin Yu, Kexin Chen, Yu Zhao, et al. FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158271.
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