Skp2-ubiquitinated 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. Chemotherapic resistance is a major obstacle in the treatment of NSCLC patients. Here, we found that 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 xenograft tumor growth of NSCLC cells. We also found that Skp2 protein is inversely correlated with MLKL protein in NSCLC tissues. Moreover, in cisplatin-resistant NSCLC cells, Skp2 protein level is increased, accompanied by a significant increase of MLKL ubiquitination and a decrease of MLKL protein level. Accordingly, the inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, Skp2 interacts with MLKL and promotes the ubiquitination and degradation of MLKL, which participates in cisplatin resistance in NSCLC cells. Our results provide evidence of a Skp2-dependent mechanism regulating MLKL degradation and involving in cisplatin-resistant in NSCLC cells, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.