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作者：Jerry
导读：紫杉醇(Paclitaxel, PTX)耐药是导致“最毒乳腺癌”—三阴性乳腺癌(triple negative breast cancer, TNBC)预后不良的重要因素，迫切需要寻找新的联合治疗靶点。
6月26日，同济大学医学院研究人员在期刊《Journal of Experimental & Clinical Cancer Research》上发表了题为“Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy”的研究论文，本研究中，研究人员发现NAE-UBC12-TRIM25-TFEB-自噬轴是调节化疗耐药型三阴性乳腺癌中自噬相关基因转录的新型机制，对于缓解PTX耐药性至关重要。 TRIM25可能是治疗化疗耐药型三阴性乳腺癌的潜在下游靶点。
https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03085-w#auth-Lin-Fang-Aff1
Background:
01
Triple-negative breast cancer refers to breast cancer that lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. TNBC is the subtype with the worst prognosis and poses a significant threat to women's health. Currently, chemotherapy and surgery are the mainstays of treatment for TNBC due to its unique molecular subtypes and lack of effective targets. However, the development of chemoresistance and low response rates (10-15%) often hinder the success of treatment. Therefore, it is of great significance to find new chemosensitization targets.
Autophagy is a highly conserved eukaryotic process that is closely related to TNBC progression and chemoresistance. Autophagosomes in tumor cells engulf damaged organelles and fuse with lysosomes, promoting protein recovery and helping to survive in malignant conditions. The level of autophagy in TNBC cells is higher than that of other subtypes. Previous studies have shown that inhibition of autophagy restores the sensitivity of TNBC cells to chemotherapy. Therefore, autophagy is a potential target for the treatment of TNBC. The transcription factor TFEB plays a key role in the regulation of the autophagy-lysosomal system. TFEB has been implicated in tumor progression by modulating the autophagic lysosomal system and even without relying on autophagy, promoting various cancer phenotypes. In a nutrient-rich state, TFEB undergoes a high degree of phosphorylation modification, and the phosphorylated amino acid sequence is recognized by the 13-3-3 protein, resulting in its sequestration in the cytoplasm. When external conditions change, such as cold, starvation, or lipopolysaccharide (LPS) treatment, TFEB rapidly dephosphorylates and shifts within the nucleus in response to these stimuli. However, there are many unknowns about the modulating role of other post-translational modifications (PTMs) of TFEB.
Research Progress
02
Since fewer studies have shown a direct relationship between TRIM25 and autophagy, the researchers first analyzed the correlation between the two in the TCGA database. The researchers observed that the expression of TRIM25 was positively correlated with autophagy-related genes such as ATG5, ATG7, and Atg12. In addition, these genes are regulated by TFEB and are associated with poor prognosis in breast cancer. BY RT-PCR, THE RESEARCHERS FOUND THAT TRIM25 OVEREXPRESSION INCREASED THE TRANSCRIPTION OF ATG5 AND LC3B, WHILE KNOCKDOWN OF TRIM25 INHIBITED THEIR TRANSCRIPTION. Immunoblotting results also showed that TRIM25 overexpression activated autophagic flow. However, no significant activation of autophagic flux was observed after transfection of the TRIM25 K117R mutant plasmid compared to transfection of the wild-type TRIM25 plasmid. In addition, no increase in autophagosome formation due to TRIM25 K117R overexpression was observed after MDC staining. Clonal formation, cell migration assays, and xenograft tumor models showed that in vitro and in vivo, wild-type TRIM25 promoted PTX chemoresistant TNBC, while TRIM25 K117R overexpression had no effect. IHC analysis showed an increase in the abundance of LC3B protein in mouse transplant tissues overexpressing wild-type TRIM25, but no significant changes were observed in mouse transplant tissues overexpressing TRIM25 K117R. These results suggest that TRIM25 reduces TNBC chemosensitivity by promoting autophagy, and acylation is essential for TRIM25 activation. Interestingly, the researchers also observed an increase in TRIM25 acylation levels in wild-type MDA-MB-231 cells under repeated low-dose PTX stimulation, while no significant changes in TRIM25 acylation levels in TRIM25 K117R mutant cells, which may represent another potential mechanism of PTX-induced autophagy.
Anthropomimesis is required for TRIM25 activation and autophagy regulation
Conclusions of the study
03
In summary, there is biomimetic activation in PTX-resistant triple-negative breast cancer. By altering the protein conformation of TRIM25, mimesis enhances its binding to macromolecular substrates. Activated TRIM25 promotes K63-linked ubiquitination and nuclear translocation of TFEB. Transcriptional activation of autophagic genes mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. TRIM25 may be a potential downstream target for the treatment of chemotherapy-resistant triple-negative breast cancer.
Resources:
https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03085-w#auth-Lin-Fang-Aff1
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