IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

Abstract

Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

The m6A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m6A-Dependent Manner

“…In addition, IU1, a small-molecule inhibitor of USP14, accelerated the degradation of a subset of proteasome substrates and suppressed cell proliferation, migration, and invasion in lung cancer and cervical cancer ( Lee et al, 2010 ; Han K.H. et al, 2019 ; Xu et al, 2020 ). The IC 50 of IU1 is 4.7 μM 5 , and concentrations of 50–100 μM IU1 have been used in multiple cancer cells ( Li H. et al, 2019 ; Xia et al, 2019 ; Sharma et al, 2020 ; Sharma and Almasan, 2020 ).…”

P22077 enhances the antitumor efficacy of Cisplatin and its mechanism

“…USP7 reportedly is involved in the development of several tumors, including esophagus cancer, myeloma, ovarian cancer and hepatocellular carcinoma. It is also highly expressed in cervical cancer [25,36]. In cancer, USP7 can stabilize MDM2 by de-ubiquitination and subsequently promote the degradation of p53 and has been suggested as an emerging new drug target for chemotherapy against cancer.…”

Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

“…In tumor cells, MDM2 can polyubiquitinate p53, leading to its proteasomal degradation, which is a major pathway altered in cancers [ 63 , 64 ]. MDM2 upregulation has been reported in various cancers, which renders it an attractive drug target for cancer therapy [ 46 , 47 , 48 , 65 ]. However, p53 mutations are frequently observed in tumors.…”