State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, Sun Yat-sen University, School of Pharmaceutical Sciences, Guangzhou, Guangdong, 510006, China.
Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, 102218, China.
Eur J Pharmacol. 2024 Aug 15;977:176697. doi: 10.1016/j.ejphar.2024.176697. Epub 2024 May 31.
Gastric cancer (GC) remains a global challenge due to the lack of early detection and precision therapies. Genkwadaphnin (DD1), a natural diterpene isolated from the bud of Flos GenkWa (Thymelaeaceae), serves as a Karyopherin β1 (KPNB1) inhibitor. In this study, we investigated the anti-tumor effect of DD1 in both cell culture and animal models. Our findings reveal that KPNB1, a protein involved in nuclear import, was highly expressed in GC tissues and associated with a poor prognosis in patients. We demonstrated that DD1, alongside the established KPNB1 inhibitor importazole (IPZ), inhibited GC cell proliferation and tumor growth by enhancing both genomic and non-genomic activity of Nur77. DD1 and IPZ reduced the interaction between KPNB1 and Nur77, resulting in Nur77 cytoplasmic accumulation and triggering mitochondrial apoptosis. The inhibitors also increased the expression of the Nur77 target apoptotic genes ATF3, RB1CC1 and PMAIP1, inducing apoptosis in GC cell. More importantly, loss of Nur77 effectively rescued the inhibitory effect of DD1 and IPZ on GC cells in both in vitro and in vivo experiments. In this study, we for the first time explored the relationship between KPNB1 and Nur77, and found KPNB1 inhibition could significantly increase the expression of Nur77. Moreover, we investigated the function of KPNB1 in GC for the first time, and the results suggested that KPNB1 could be a potential target for cancer therapy, and DD1 might be a prospective therapeutic candidate.
胃癌（GC）仍然是一个全球性的挑战，因为缺乏早期检测和精准治疗。Genkwadaphnin（DD1）是从 Flos GenkWa（卫矛科）芽中分离出来的天然二萜，是核输入载体蛋白β1（KPNB1）的抑制剂。在这项研究中，我们研究了 DD1 在细胞培养和动物模型中的抗肿瘤作用。我们的研究结果表明，核输入载体蛋白 KPNB1 在 GC 组织中高表达，并与患者预后不良相关。我们发现，DD1 与已建立的 KPNB1 抑制剂 importazole（IPZ）一起，通过增强 Nur77 的基因组和非基因组活性，抑制 GC 细胞增殖和肿瘤生长。DD1 和 IPZ 减少了 KPNB1 和 Nur77 之间的相互作用，导致 Nur77 细胞质积累并触发线粒体凋亡。抑制剂还增加了 Nur77 靶凋亡基因 ATF3、RB1CC1 和 PMAIP1 的表达，诱导 GC 细胞凋亡。更重要的是，Nur77 的缺失有效地挽救了 DD1 和 IPZ 在体外和体内实验中对 GC 细胞的抑制作用。在这项研究中，我们首次探讨了 KPNB1 和 Nur77 之间的关系，并发现 KPNB1 抑制可显著增加 Nur77 的表达。此外，我们首次研究了 KPNB1 在 GC 中的功能，结果表明 KPNB1 可能是癌症治疗的潜在靶点，DD1 可能是一种有前途的治疗候选物。
