Repression of apelin Furin cleavage sites provides antimetastatic strategy in colorectal cancer

The adipokine apelin has been directly implicated in various physiological processes during embryogenesis and human cancers. Nevertheless, the importance of the conversion of its precursor proapelin to mature apelin in tumorigenesis remains unknown. In this study, we identify Furin as the cellular proprotein convertase responsible for proapelin cleavage. We explore the therapeutic potential of targeting proapelin cleavage sites in metastatic colorectal cancer by introducing apelin-dm, a modified variant resulting from alteration in proapelin cleavage sites. Apelin-dm demonstrates efficacy in inhibiting tumor growth, promoting cell death, suppressing angiogenesis, and early colorectal liver metastasis events. Proteomic analysis reveals reciprocal regulation between apelin and apelin-dm on proteins associated with clinical outcomes in colon cancer patients. Apelin-dm emerges as a modulator of apelin receptor dynamics, influencing affinity, internalization, and repression of apelin signaling linked to various protein kinases. Pharmacokinetic and toxicity assessments confirm the specificity, safety, and stability of apelin-dm, as well as its facile hepatic metabolism. These findings position targeting proapelin cleavage as a promising therapeutic strategy against metastatic colorectal cancer, paving the way for further clinical exploration.

脂肪细胞因子apelin已被证实直接参与胚胎发生及人类癌症发生过程中的多种生理进程。然而，其前体蛋白前apelin（proapelin）转化为成熟apelin的过程在肿瘤发生中的重要性仍未明确。本研究鉴定出弗林蛋白酶（Furin）为负责切割前apelin的细胞内蛋白转换酶。我们通过引入apelin-dm——一种通过改造前apelin切割位点得到的修饰变体——探索靶向前apelin切割位点在转移性结直肠癌中的治疗潜力。Apelin-dm可有效抑制肿瘤生长、促进细胞死亡、抑制血管生成以及早期结直肠癌肝转移事件的发生。蛋白质组学分析显示，apelin与apelin-dm可对结直肠癌患者临床预后相关蛋白产生双向调控作用。Apelin-dm可作为Apelin受体（apelin receptor）动态平衡的调控因子，影响其亲和力、内化过程，并抑制与多种蛋白激酶相关的apelin信号通路。药代动力学与毒性评估证实了apelin-dm的特异性、安全性与稳定性，同时其肝脏代谢过程简便易行。上述研究结果表明，靶向前apelin切割是一种极具前景的转移性结直肠癌治疗策略，为后续临床探索铺平了道路。