MEX3A Mediates p53 Degradation to Suppress Ferroptosis and Facilitate Ovarian Cancer Tumorigenesis

Abstract

Epithelial ovarian cancer (OC) is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major OC histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other OC subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wildtype (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing OC remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA binding domain, was critical for tumorigenesis in WT p53-expressing OC. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in OC cells expressing WT p53.

STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway

“…Previous studies revealed that p53 inhibited the expression of SLC7A11, which in turn inhibited cystine uptake and induced ferroptosis [ 32 ]. In OC, MEX3A mediated degradation of p53 to inhibit ferroptosis and promote OC tumor progression [ 33 ]. In another study on the application of PARP inhibitors in OC, researchers found that PARP inhibition promoted ferroptosis by inhibiting SLC7A11 in a p53-dependent manner [ 34 ].…”

From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer

“…Unlike traditional apoptosis, necrosis, and autophagy, ferroptosis is due to excess intracellular iron ions, leading to oxidative stress and cell death, and has been linked to the development of many cancers, including OC [ 175 , 176 ]. MEX3A is an evolutionarily conserved RNA binding protein (RBP) involved in cellular ferroptosis and is involved in various tumorigenesis by regulating mRNA stability, transport and translocation [ 177 – 179 ]. On the one hand, MEX3A can affect the distribution and utilization of intracellular iron ions by inhibiting the expression of iron metabolism-related genes FTH1 and FPN and regulating intracellular iron ion transport and storage, thus reducing the level of intracellular free iron ions and alleviating oxidative stress and cell death; On the other hand, MEX3A can also cause p53 protein degradation and enhance tumorigenesis [ 179 ].…”

Machine learning developed a fibroblast-related signature for predicting clinical outcome and drug sensitivity in ovarian cancer

“…[2] Characterized by high heterogeneous and high aggression, OC patients experience a poor clinical outcome having a 5-year survival rate less than 50%. [3,4] Despite immunotherapy as a promising modality for many cancer, [5] the evidences about OC response to immunotherapy are limited. Moreover, there are few clinical markers that can effectively predict the prognosis of OC patients.…”