Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Cell Death Dis. 2022 Mar 30;13(3):285. doi: 10.1038/s41419-022-04727-7.
The incidence of lung cancer is increasing worldwide. Although great progress in lung cancer treatment has been made, the clinical outcome is still unsatisfactory. Tripartite motif (TRIM)-containing proteins has been shown to be closely related to tumor progression. However, the function of TRIM46 in lung cancer is largely unknown. Here, TRIM46 amplification was found in lung adenocarcinoma (LUAD) tissues and TRIM46 amplification was significantly associated with a poor survival rate. Overexpression of wild type TRIM46 increased the proliferation of LUAD cells and glycolysis, promoted xenografts growth, and enhanced cisplatin (DDP) resistance of LUAD cells via increased ubiquitination of pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) and upregulation of p-AKT. In contrast, overexpression of RING-mutant TRIM46 did not show any effects, suggesting the function of TRIM46 was dependent on the E3 ligase activity. Furthermore, we found that TRIM46 promoted LUAD cell proliferation and DDP resistance by enhancing glycolysis. PHLPP2 overexpression reversed the effects of TRIM46 overexpression. Amplification of TRIM46 also promoted LUAD growth and enhanced its DDP resistance in a patient-derived xenograft (PDX) model. In conclusion, our data highlight the importance of TRIM46/PHLPP2/AKT signaling in lung cancer and provide new insights into therapeutic strategies for lung cancer.
肺癌的发病率在全球范围内呈上升趋势。尽管在肺癌治疗方面取得了巨大进展，但临床疗效仍不尽如人意。三结构域蛋白（TRIM）家族蛋白与肿瘤的发生发展密切相关。然而，TRIM46 在肺癌中的作用尚不清楚。本研究发现 TRIM46 在肺腺癌（LUAD）组织中扩增，并且 TRIM46 扩增与生存率降低显著相关。野生型 TRIM46 的过表达可增加 LUAD 细胞的增殖和糖酵解，促进异种移植瘤的生长，并通过增加 PH 结构域富含亮氨酸重复蛋白磷酸酶 2（PHLPP2）的泛素化和 AKT 的磷酸化来增强 LUAD 细胞对顺铂（DDP）的耐药性。相比之下，过表达 RING 突变型 TRIM46 则没有显示出任何效果，这表明 TRIM46 的功能依赖于 E3 连接酶的活性。此外，我们发现 TRIM46 通过增强糖酵解促进 LUAD 细胞增殖和 DDP 耐药性。PHLPP2 的过表达逆转了 TRIM46 过表达的作用。TRIM46 的扩增也促进了 PDX 模型中 LUAD 的生长并增强了其对 DDP 的耐药性。综上所述，我们的数据强调了 TRIM46/PHLPP2/AKT 信号通路在肺癌中的重要性，并为肺癌的治疗策略提供了新的见解。
