Xinxin Ci

UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer

Abstract Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.

Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells

Ovarian cancer (OC) is a common malignant tumor with the greatest mortality rate among gynecological tumors. Tiliroside (TIL) is a glycosidic dietary flavonoid with various pharmacological activities. The purpose of this study was to investigate the exact mechanism by which TIL eliminates OC cells. In vitro, TIL exerted anti-tumor activities by inducing cell death and inhibiting the invasion and migration of A2780 and OVCAR8 cells. Additionally, the suppressive effect of TIL on OC cells was mainly due to the induction of ferroptosis, as demonstrated by the fact that only ferroprostatin-1 (Fer-1) significantly inhibited the anti-tumor activity of TIL, with the accumulation of ROS, MDA, and Fe Our research revealed that TIL simultaneously targets AKR1B1 and modulates iron metabolism, thereby inducing ferroptosis and improving anti-tumor efficacy. As a novel drug, TIL is promising for OC treatment.