Department of Gastroduodenal and Pancreatic Surgery, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, United States.
Neoplasma. 2019 May 23;66(3):481-486. doi: 10.4149/neo_2018_181016N772. Epub 2019 Mar 7.
Jab1 is a vital subunit of the CSN family and is reported to be overexpressed in numerous cancer types. Due to the importance of Jab1/CSN5 in cancer cell proliferation and survival, Jab1 is considered a promising therapeutic target. Therefore, we evaluated the anticancer effect of the novel Jab1 inhibitor CSN5i-3 in breast cancer cells. In our study, we found that Jab1 was overexpressed in breast cancer tissues and was correlated with poor prognosis in human breast cancer patients. An MTS assay revealed that CSN5i-3 suppressed cell proliferation in the breast cancer cell lines BT474 and SKBR3. We also found that CSN5i-3 significantly induced apoptosis and G1 phase cell cycle arrest in breast cancer cells. A mechanistic investigation revealed that CSN5i-3 inhibited Jab1 expression and increased the level of the apoptosis marker cleaved PARP and the cell-cycle-related protein p27 in BT474 and SKBR3 cells. A nude mouse xenograft model also indicated that CSN5i-3 exerted a potent anticancer effect in vivo. Overall, our study suggested that the Jab1 inhibitor CSN5i-3 might be a promising agent for the treatment of breast cancer in humans and should be studied further.
Jab1 是 CSN 家族的一个重要亚基，据报道在许多癌症类型中过表达。由于 Jab1/CSN5 在癌细胞增殖和存活中的重要性，Jab1 被认为是一个有前途的治疗靶点。因此，我们评估了新型 Jab1 抑制剂 CSN5i-3 在乳腺癌细胞中的抗癌作用。在我们的研究中，我们发现 Jab1 在乳腺癌组织中过表达，并与人类乳腺癌患者的不良预后相关。MTS 分析表明，CSN5i-3 抑制乳腺癌细胞系 BT474 和 SKBR3 的细胞增殖。我们还发现 CSN5i-3 显著诱导乳腺癌细胞凋亡和 G1 期细胞周期停滞。机制研究表明，CSN5i-3 抑制 Jab1 表达并增加 BT474 和 SKBR3 细胞中凋亡标志物 cleaved PARP 和细胞周期相关蛋白 p27 的水平。裸鼠异种移植模型也表明 CSN5i-3 在体内具有很强的抗癌作用。总的来说，我们的研究表明，Jab1 抑制剂 CSN5i-3 可能是治疗人类乳腺癌的一种有前途的药物，应进一步研究。
