PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 21, 2024

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance carcinoma remains to be elucidated. Here, we identify PJA1 as key E3 ubiquitin ligase involved that highly expressed nonresponse docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis cells. Mechanistically, promotes degradation of mitochondrial protein PGAM5 increasing its K48-linked ubiquitination at K88, which further DRP1 phosphorylation S637 and reduced reactive oxygen species production, resulting suppression antitumour immune response. knockdown fully restores sensitization effect knockdown. Moreover, pharmacological targeting small molecule inhibitor RTA402 enhances sensitivity vitro vivo. Clinically, high expression indicates inferior survival poor clinical efficacy TPF IC patients. Our study emphasizes essential role ligases regulating provides therapeutic strategies based on ubiquitin-proteasome system.

Язык: Английский

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Efficacy and safety of Anlotinib in combination with gemcitabine and cisplatin as a first‐line treatment for recurrent or metastatic nasopharyngeal carcinoma: A single‐arm clinical trial

International Journal of Cancer, Год журнала: 2025, Номер unknown

Опубликована: Янв. 18, 2025

Abstract The effectiveness and safety of combining anlotinib with gemcitabine cisplatin in the first‐line treatment recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) have not been definitively established. This research seeks to investigate potential benefits risks utilizing this combination therapy management R/M NPC. involved 22 individuals diagnosed NPC who had undergone any previous treatment. These patients were administered a concomitant anlotinib, gemcitabine, cycles occurring every 3 weeks. primary focus study was assess progression‐free survival (PFS), while secondary endpoints included overall (OS), disease control rate (DCR), objective response (ORR). findings revealed that median PFS duration for receiving GPA regimen as 12.6 months, 95% confidence interval (CI): 0.1 25.2. OS reported 37.4 CI: 28.0 46.8. DCR 95.5%, ORR 63.6%. Anlotinib has demonstrated degree initial NPC, maintaining an acceptable level safety.

Язык: Английский

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The prognostic value of boost dose in residual cervical lymph nodes in nasopharyngeal carcinoma patients after intensity-modulated radiotherapy: a retrospective study

BMC Cancer, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 7, 2025

Язык: Английский

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The E3 ligase NEURL3 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma by promoting vimentin degradation

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Янв. 9, 2024

Abstract Background Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to initiation progression NPC. However, precise regulatory mechanism behind these processes remains poorly understood. Methods Bisulfite pyrosequencing, RT-qPCR, western blot, immunohistochemistry were used test expression level NEURL3 its clinical significance. The biological function was examined both vitro vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, ubiquitin assays performed explore NEURL3. Results promoter region , encoding an E3 ligase, obviously hypermethylated, leading downregulated Clinically, NPC a low indicated unfavorable prognosis prone develop distant metastasis. Overexpression could suppress epithelial mesenchymal transition metastasis cells Mechanistically, promoted Vimentin degradation by increasing K48-linked polyubiquitination at lysine 97. Specifically, restoration fully reverse tumor suppressive effect overexpression cells. Conclusions Collectively, our study uncovers novel which inhibits metastasis, thereby providing promising therapeutic target for treatment.

Язык: Английский

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DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Июль 8, 2024

Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, mechanisms underlying lack benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating response TPF therapy in NPC patients. promotes resistance metastasis cells vitro vivo. Mechanistically, serves scaffold protein that facilitates interaction between USP10 G3BP1, leading elimination K48-linked ubiquitin moieties from Lys76 G3BP1. This process helps prevent degradation G3BP1 via ubiquitin‒proteasome pathway formation stress granule (SG)-like structures. Moreover, knockdown successfully reversed SG-like structures oncogenic effects DCAF7. Significantly, increased levels showed high risk metastasis, elevated linked an unfavorable prognosis. The study reveals crucial offers further understanding how develops NPC. DCAF7-USP10-G3BP1 axis contains potential targets biomarkers treatment.

Язык: Английский

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