PJA1泛素化调控PGAM5-DRP1通路抑制细胞焦亡导致鼻咽癌化疗耐药的机制研究

化疗耐药是导致肿瘤治疗失败的重要原因，且耐药患者更易复发或转移，制约鼻咽癌生存率的提升。我们前期芯片发现E3泛素连接酶PJA1在鼻咽癌化疗耐药中起核心作用，围绕“PJA1是否以及如何引起化疗耐药”这一科学问题，开展预实验发现：敲低PJA1增强鼻咽癌细胞对多西他赛化疗敏感性，过表达PJA1抑制多西他赛诱导的细胞焦亡；机制上PJA1能结合并泛素化降解PGAM5蛋白，PGAM5与DRP1蛋白互作并促进化疗诱导的焦亡，但具体调控关系未明。据此，我们提出假说：PJA1泛素化降解PGAM5蛋白，解除PGAM5去磷酸化激活DRP1及下游通路，进而抑制GSDME介导的焦亡，导致鼻咽癌多西他赛化疗耐药。围绕上述假说，本课题拟阐明PJA1泛素化调控PGAM5/DRP1通路抑制焦亡导致鼻咽癌化疗耐药的分子机制；并明确PJA1在诱导化疗疗效预测及逆转化疗耐药中的价值，从而为鼻咽癌个体化治疗提供分子指标和干预靶点。

Chemoresistance is an important cause of tumor treatment failure, and drug-resistant patients are more likely to develop relapse or metastasis, which restricts the improvement of survival rate of nasopharyngeal carcinoma (NPC). Our previous microarray found that E3 ubiquitin ligase PJA1 plays a core role in NPC chemoresistance. Centring on the scientific question "whether and how PJA1 causes chemoresistance", we conducted pre-experiment and found that knockdown of PJA1 enhanced the sensitivity of NPC cells to docetaxel chemotherapy, and overexpression of PJA1 inhibited docetaxel-induced cell pyroptosis. Mechanically, PJA1 can bind and promote PGAM5 protein ubiquitination and degradation, and PGAM5 interacts with DRP1 protein and promotes chemotherapy-induced pyroptosis, but the specific regulatory relationship is unclear. Based on this, we hypothesized that PJA1 ubiquitinates to degrade PGAM5 protein, removes the dephosphorylation by PGAM5 on DRP1, and then inactivates DRP1 and its downstream pathway, thereby inhibiting GSDME-mediated pyroptosis and leading to docetaxel chemoresistance in NPC. Focusing on the above hypotheses, this study aims to clarify the molecular mechanism of PJA1 ubiquitination regulating the PGAM5/DRP1 pathway to inhibit cell pyroptosis and result in NPC chemoresistance. Moreover, the value of PJA1 expression in predicting the efficacy of induction chemotherapy and the role of PJA1 inhibitor in reversing NPC chemoresistance was clarified, so as to provide molecular indicators and intervention targets for NPC individualized treatment.