Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Commun Biol. 2023 Aug 2;6(1):805. doi: 10.1038/s42003-023-05166-6.
Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.
非小细胞肺癌（NSCLC）是最常见的癌症类型，也是癌症相关死亡的主要原因。化疗耐药是治疗 NSCLC 患者的主要障碍。在这里，我们发现 E3 连接酶 Skp2 在人 NSCLC 组织和细胞系中过度表达，同时伴有坏死相关调节剂 MLKL 的下调。Skp2 的敲低抑制了 NSCLC 细胞的活力、锚定非依赖性生长和体内肿瘤发展。我们还发现 Skp2 蛋白在 NSCLC 组织中与 MLKL 呈负相关。此外，Skp2 在顺铂耐药的 NSCLC 细胞中增加，并伴有 MLKL 泛素化和降解的上调。因此，抑制 Skp2 可部分恢复 MLKL 的表达，并在体外和体内使 NSCLC 细胞对顺铂敏感。在机制上，Skp2 相互作用并促进顺铂耐药的 NSCLC 细胞中 MLKL 泛素化介导的降解。我们的研究结果提供了 Skp2 依赖性机制调节 MLKL 降解和顺铂耐药的证据，表明靶向 Skp2-泛素化 MLKL 降解可能克服 NSCLC 的化疗耐药性。
