| Autor: |
Cong, Yu, Cui, Xin, Shi, Yaqian, Pan, Xinxing, Huang, Ke, Geng, Zhe, Xu, Pengfei, Ge, Lili, Zhu, Jin, Xu, Juan, Jia, Xuemei |
| Zdroj: |
Molecular & Cellular Biochemistry; Dec2024, Vol. 479 Issue 12, p3405-3424, 20p |
| Abstrakt: |
The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells. Our study mainly investigated the role and mechanism of the E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) in the progression of ovarian cancer. As a tumor suppressor, TRIM3 interact directly with LDHA and promotes the ubiquitination and degradation of LDHA, which plays a crucial role in the conversion of pyruvate and NADH to L-lactate and NAD in the final step of anaerobic glycolysis, thereby inhibiting glycolysis in ovarian cancer cells. Furthermore, overexpression of TRIM3 also reduces the phosphorylation of AKT independently of the interaction between TRIM3 and LDHA. In summary, our findings demonstrated that TRIM3 could inhibit ovarian cancer progression by downregulating LDHA and suppressing the AKT signaling pathway. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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