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Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.

ABSTRACT: 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.

SUBMITTER: Zhou H

PROVIDER: S-EPMC10397346 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.

Zhou Huiling H Zhou Li L Guan Qing Q Hou Xuyang X Wang Cong C Liu Lijun L Wang Jian J Yu Xinfang X Li Wei W Liu Haidan H

Communications biology 20230802 1

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 tha ...[more]

PMID: 37532777

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Project description:BackgroundLoss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy.MethodsWe investigated the mutational landscape of LKB1 mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling of LKB1 wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay.ResultsBy using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched "hot" TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded "cold" TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling.ConclusionLKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from "hot" TME to "cold" TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy.

Dataset Information

Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.

Publications

Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.

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