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

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

  • Commun Biol. 2023 Aug 2;6(1):805. doi: 10.1038/s42003-023-05166-6.
Huiling Zhou # 1 2,  Li Zhou # 3,  Qing Guan 1 2,  Xuyang Hou 1 2,  Cong Wang 2,  Lijun Liu 1 2,  Jian Wang 1 2,  Xinfang Yu 4,  Wei Li 5,  Haidan Liu 6 7
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2 Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 3 Department of Pathology, National Clinical Research Center for Geriatric Disorders, The Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 4 Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 5 Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • 6 Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • 7 Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 37532777 DOI: 10.1038/s42003-023-05166-6
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.

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