Targeting KPNB1 with genkwadaphnin suppresses gastric cancer progression through the Nur77-mediated signaling pathway

• Published in: European journal of pharmacology 2024-08, Vol.977, p.176697, Article 176697
• Main Authors: Zhang, Chenxi, Wang, Xiaojuan, Cai, Guodi, Wang, Hong, Liu, Qianqian, Ma, Shuai, Sun, Huizi, An, Yana, Miao, Miaomiao, Yin, Sheng, Liu, Peiqing, Wang, Xiaolu, Wang, Junjian
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; beta Karyopherins - genetics; beta Karyopherins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; Diterpenes - pharmacology; Diterpenes - therapeutic use; Female; Gastric cancer; Gene Expression Regulation, Neoplastic - drug effects; Genkwadaphnin; Humans; KPNB1; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Nur77; Signal Transduction - drug effects; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.176697

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. [Display omitted] •KPNB1 was highly expressed in gastric cancer tissues and associated with a poor patient prognosis.•KPNB1 inhibitor DD1 potently suppresses GC cell survival and tumor growth.•Nur77 acts as a key determinant of the function of KPNB1 in GC.•KPNB1 represents a potential therapeutic target in GC.•DD1 can be a promising therapeutic drug for GC.