Mechanism of NUMBL enhancing axitinib resistance in clear cell renal cell carcinoma by UCHL1-mediated deubiquitination of MMP9.

ABSTRACT: The 5-year survival rate for metastatic clear cell renal cell carcinoma (ccRCC) is only 8%. Although antiangiogenic therapy like axitinib is the first-line treatment, tumors often develop resistance rapidly. This study investigates the role of NUMB-like endocytic adaptor protein (NUMBL) in this resistance. We found that NUMBL expression is upregulated in axitinib-resistant ccRCC cells. Knocking down NUMBL in a resistant 769P cell line significantly reduced the axitinib IC₅₀ from 218.3 μM to 113.2 μM, thereby restoring drug sensitivity. Mechanistically, NUMBL upregulates ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 then interacts with and deubiquitinates matrix metalloproteinase 9 (MMP9), leading to MMP9 protein stabilization and increased expression. This cascade ultimately

SUBMITTER: Wang Z 

PROVIDER: S-EPMC12704280 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature