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Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells
Huiling Zhou1,2, Li Zhou3, Qing Guan1,2
1Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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.
Insights
Overexpressed Skp2 E3 ligase drives chemoresistance in non-small cell lung cancer (NSCLC) by degrading MLKL. Targeting Skp2 may restore sensitivity to chemotherapy in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) presents a significant global health challenge due to its high prevalence and mortality.
- Chemotherapeutic resistance remains a critical barrier to effective NSCLC treatment, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of the E3 ligase Skp2 in NSCLC chemoresistance.
- To elucidate the molecular mechanism linking Skp2, MLKL, and cisplatin resistance in NSCLC.
Main Methods:
- Analysis of Skp2 and MLKL expression in NSCLC tissues and cell lines.
- Skp2 knockdown experiments in NSCLC cells.
- Assessment of cell viability, anchorage-independent growth, and in vivo tumor development.
- Investigation of MLKL ubiquitination and degradation.
- Evaluation of Skp2 inhibition's effect on cisplatin sensitivity in vitro and in vivo.
Main Results:
- Skp2 is overexpressed in NSCLC and negatively correlated with MLKL.
- Skp2 knockdown inhibits NSCLC cell proliferation and tumor growth.
- Skp2 promotes MLKL ubiquitination and degradation, particularly in cisplatin-resistant cells.
- Inhibition of Skp2 restores MLKL levels and sensitizes NSCLC cells to cisplatin.
Conclusions:
- Skp2-mediated degradation of MLKL is a key mechanism driving cisplatin resistance in NSCLC.
- Targeting the Skp2-MLKL axis offers a potential therapeutic strategy to overcome chemoresistance in NSCLC.
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