He Jingliang, Guo Jingli, Liu Shunfang, Li Hanxue, Ma Yuanyuan, Ma Shaojie, Hu Zhongke, Zhao Wensi, Tan Minjia, Liu Wei, Liu Bin
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Signal. 2025 Jun;130:111665. doi: 10.1016/j.cellsig.2025.111665. Epub 2025 Feb 20.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, emphasizing the urgent need for novel therapeutic strategies. In this study, we investigate the anti-tumor potential of CC-885, a cereblon (CRBN) modulator known for its efficacy in targeting neoplastic cells through proteasomal degradation pathways. Our findings demonstrate that CC-885 exhibits potent anti-tumor activity against HCC. In vitro assays revealed that CC-885 significantly inhibits the proliferation, migration, and invasion of HCC cells. These effects were corroborated in vivo, where CC-885 markedly suppressed tumor growth and angiogenesis in chick embryos and impeded the progression of orthotopic liver tumors in murine models. Mechanistically, CC-885 selectively reduces GOLM1 protein levels via ubiquitin-mediated proteasomal degradation. Knockdown of GOLM1 recapitulated the anti-proliferative effects of CC-885, while overexpression of GOLM1 conferred resistance to CC-885-induced apoptosis and growth inhibition. Further investigation revealed that CC-885 facilitates the interaction between GOLM1 and the E3 ubiquitin ligase CRBN, promoting the ubiquitination and subsequent degradation of GOLM1. Transcriptomic analyses showed that both CC-885 treatment and GOLM1 knockdown modulate critical pathways involved in apoptosis. These findings position CC-885 as a promising therapeutic candidate for HCC, acting primarily through CRBN-dependent degradation of GOLM1, and support its further development for clinical application.
肝细胞癌（HCC）仍然是癌症相关死亡的主要原因，这凸显了对新型治疗策略的迫切需求。在本研究中，我们探究了CC-885的抗肿瘤潜力，CC-885是一种cereblon（CRBN）调节剂，因其通过蛋白酶体降解途径靶向肿瘤细胞的功效而闻名。我们的研究结果表明，CC-885对HCC具有强大的抗肿瘤活性。体外试验显示，CC-885显著抑制HCC细胞的增殖、迁移和侵袭。这些作用在体内得到了证实，CC-885在鸡胚中显著抑制肿瘤生长和血管生成，并在小鼠模型中阻碍原位肝肿瘤的进展。从机制上讲，CC-885通过泛素介导的蛋白酶体降解选择性降低GOLM1蛋白水平。敲低GOLM1可重现CC-885的抗增殖作用，而GOLM1的过表达赋予对CC-885诱导的凋亡和生长抑制的抗性。进一步研究表明，CC-885促进GOLM1与E3泛素连接酶CRBN之间的相互作用，促进GOLM1的泛素化及随后的降解。转录组分析表明，CC-885处理和GOLM1敲低均调节参与凋亡的关键途径。这些发现将CC-885定位为HCC的一种有前景的治疗候选药物，主要通过CRBN依赖性降解GOLM1发挥作用，并支持其进一步开发用于临床应用。
