Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
Cell Death Dis. 2021 Jul 31;12(8):755. doi: 10.1038/s41419-021-04043-6.
Lung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.
肺癌是全球癌症相关死亡的主要原因，其中非小细胞肺癌（NSCLC）是主要亚型，约占肺癌病例的 85%。尽管人们为治疗肺癌做出了巨大努力，但迄今为止尚未发现经过验证的方法。考虑到β，β-二甲基丙烯酰基-紫草素（ALCAP2），这是一种从紫草根中分离出来的天然小分子化合物。我们发现 ALCAP2 可在体外显著抑制肺腺癌（LUAD）细胞的增殖和转移，因为它可以诱导细胞凋亡并阻止细胞周期。ALCAP2 还显著抑制了小鼠肿瘤的体积，而在体内没有引起明显的毒性。从机制上讲，我们揭示了用 ALCAP2 处理的细胞可以通过上调 E3 连接酶 NEDD4L 来抑制β-连环蛋白的核易位，促进泛素与β-连环蛋白的结合，最终影响存活素、细胞周期蛋白 D1 和 MMP9 等基因的 wnt 触发转录。因此，我们的研究结果表明，用 ALCAP2 靶向致癌基因β-连环蛋白可以抑制 LUAD 细胞的增殖和转移，因此，ALCAP2 可能是 LUAD 治疗的一种新的候选药物。
