Skp2介导的MLKL降解在非小细胞肺癌细胞中赋予顺铂耐药性。
Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.
发表日期：2023 Aug 02
作者：
Huiling Zhou, Li Zhou, Qing Guan, Xuyang Hou, Cong Wang, Lijun Liu, Jian Wang, Xinfang Yu, Wei Li, Haidan Liu
来源：
Cell Death & Disease
摘要：
非小细胞肺癌(NSCLC)是最常见的癌症类型和导致癌症相关死亡的主要原因。化疗抵抗是治疗NSCLC患者的主要障碍。在这里，我们发现E3连接酶Skp2在人类NSCLC组织和细胞系中过度表达，伴随着坏死相关调节因子MLKL的下调。Skp2的沉默抑制了NSCLC细胞的存活能力、无锚定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NSCLC细胞中增加，伴随着MLKL泛素化和降解的增加。因此，Skp2的抑制部分恢复了MLKL，并使NSCLC细胞对顺铂在体内外敏感。在机制上，Skp2与顺铂耐药NSCLC细胞中的MLKL相互作用并促进泛素化介导的降解。我们的结果提供了一个Skp2依赖性机制调控MLKL降解和顺铂抵抗的证据，表明靶向Skp2-泛素化的MLKL降解可能克服NSCLC化疗抵抗。© 2023. 作者.
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.© 2023. The Author(s).