Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Biomed Pharmacother. 2023 Oct;166:115359. doi: 10.1016/j.biopha.2023.115359. Epub 2023 Aug 28.
Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.
吉西他滨（Gem）是胰腺癌的一线化疗药物，但获得性耐药也阻碍了其应用。因此，研究 Gem 耐药性对于提高 Gem 的治疗效果至关重要。作为一种去泛素化酶，泛素特异性蛋白酶 8（USP8）被证明在几种癌症的肿瘤发生过程中发挥着重要作用；然而，USP8 对胰腺癌 Gem 耐药性的影响在很大程度上仍不清楚。在本研究中，我们观察到 USP8 在胰腺癌患者中的表达增加，它与 Gem 化疗的复发有关，并且 Gem 的应用可以诱导 USP8 的表达。此外，USP8 通过调节细胞活力和细胞凋亡在体内和体外均促进 Gem 耐药性。此外，USP8 增强了 Nrf2 信号的激活，这依赖于其去泛素酶能力。最后，我们表明 USP8 与 Nrf2 直接相互作用，并从 Nrf2 上去泛素化 K48 连接的多泛素链，稳定 Nrf2 的表达。总之，本文揭示了 USP8 在 Gem 耐药性中的作用，并提出 USP8 可能是胰腺癌的潜在治疗靶点。
