PDF(Pubmed)
Abstract：
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world, which is frequently diagnosed at a late stage. HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy. Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development. Carfilzomib (CFZ) is a second-generation proteasome inhibitor, which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers. However, the underlying mechanism of CFZ on HCC is still unclear. Here, we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition. We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum (ER) stress and activate JNK/p38 MAPK signaling in HCC cells, thus inducing cell death in HCC cells. Moreover, CFZ significantly inhibits HCC cell growth in a xenograft mouse model. Collectively, our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling, thus inhibiting HCC cell and tumor growth. This indicates that CFZ has the potential as a therapeutic drug for HCC.
摘要：
肝细胞癌（HCC）是世界上最常见和最致命的癌症之一，经常在晚期被诊断出来。由于缺乏有效的治疗策略，HCC患者的预后较差。批准的药物再利用是加速药物发现的一种方式，可以显着降低药物开发成本。卡非佐米（CFZ）是第二代蛋白酶体抑制剂，它对多发性骨髓瘤非常有效，并且据报道具有针对多种癌症的潜在抗肿瘤活性。然而,CFZ对HCC的潜在机制尚不清楚。这里,我们表明CFZ通过细胞周期阻滞在G2/M期抑制HCC细胞的增殖，并通过抑制上皮-间质转化抑制HCC细胞的迁移和侵袭。我们还发现，CFZ促进活性氧的产生，以诱导内质网（ER）应激和激活JNK/p38MAPK信号在肝癌细胞，从而诱导HCC细胞死亡。此外，CFZ在异种移植小鼠模型中显著抑制HCC细胞生长。总的来说，我们的研究阐明，CFZ损害线粒体功能，激活内质网应激和JNK/p38MAPK信号，从而抑制HCC细胞和肿瘤生长。这表明CFZ具有作为HCC治疗药物的潜力。
