SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53
SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53
复制标题
DOI：
10.1038/s41388-023-02843-y
复制
发表时间：
2023-09-22
期刊：
影响因子：
8
通讯作者：
Chen, Leifeng
中科院分区：
文献类型：
--
作者：
Che, Ben;Du, Yunyan;Chen, Leifeng
胰腺癌细胞经历复杂的代谢重编程以维持其生存和增殖。 p53 在肿瘤细胞铁死亡中发挥双重作用。然而，野生型 p53 激活在促进胰腺癌细胞铁死亡中的确切作用和机制仍不清楚。在本研究中，我们应用生物信息学工具对临床组织样本数据库进行分析，观察到胰腺癌组织中溶质载体家族35成员F2（SLC35F2）的表达显着上调。我们的临床研究表明，SLC35F 表达升高与不良生存结果相关。通过多组学分析，我们发现 SLC35F2 影响转录组并抑制胰腺癌细胞的铁死亡。此外，我们的研究结果揭示了p53在体外和体内介导SLC35F2介导的铁死亡中的关键参与。 SLC35F2 通过促进 TRIM59 介导的 p53 降解来抑制铁死亡。进一步的机制研究表明，SLC35F2 与 TRIM59 的 E3 泛素连接酶 SYVN1 竞争性相互作用，从而稳定 TRIM59 的表达，从而促进 p53 降解。利用蛋白质 3D 结构分析和药物筛选，我们确定了盐酸伊立替康和二甲苯磺酸拉帕替尼作为靶向 SLC35F2 的化合物，增强了咪唑酮erastin (IKE) 在野生型 p53 患者来源的异种移植 (PDX) 模型中的抗肿瘤作用。然而，在p53突变体PDX模型中，盐酸伊立替康和二甲苯磺酸拉帕替尼并没有改变肿瘤异种移植模型对IKE触发的铁死亡的敏感性。总之，我们的工作建立了一种新机制，其中 SLC35F2-SYVN1-TRIM59 轴通过抑制内源性 p53 来关键调节胰腺癌细胞的铁死亡。因此，SLC35F2 成为治疗胰腺癌的有前途的治疗靶点。
Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.