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<p>Cathepsin L (Cat L), a lysosomal endopeptidase, is overexpressed in human renal clear carcinoma (RCC); however, its impact on apoptosis remains unclear. Results revealed that inhibition (SID, a specific inhibitor), knockdown (siRNA), or knockout of Cat L sensitizes human carcinoma cells to anticancer drugs-mediated apoptosis through the downregulation of Bcl-xL and Survivin at the post-translational level. Moreover, combined treatment with SID and sorafenib reduced the tumor growth in a xenograft model. Deletion of Cat L induced Parkin stabilization by increasing DUB3 expression at the transcriptional level. Parkin knockdown significantly prevented SID-induced Bcl-xL downregulation. Conversely, ectopic expression of Parkin suppressed Bcl-xL expression. Furthermore, SID-mediated Parkin upregulation inhibited USP53 deubiquitinase protein expression, leading to the degradation of Survivin expression through its ubiquitination. Parkin directly ubiquitinated Bcl-xL and USP53, but not Survivin. These results demonstrate that inhibition of Cat L enhances anticancer drugs-induced apoptosis through Parkin-mediated ubiquitination of Bcl-xL and USP53. Moreover, the downregulation of USP53 suppressed the expression of Survivin. Therefore, Cat L can be considered a potential candidate molecular target for the treatment of RCC.</p>

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Cathepsin L deletion enhances sensitivity to anticancer drugs through Parkin-mediated ubiquitination of Bcl-xL and USP53-induced Survivin destabilization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Seung Un Seo,
  • Seon Min Woo,
  • Yongsoo Kwon,
  • Shin Kim,
  • Hyun-Shik Lee,
  • Sang Hyun Kim,
  • Kyoung-jin Min,
  • Simmyung Yook,
  • Taeg Kyu Kwon

摘要

Cathepsin L (Cat L), a lysosomal endopeptidase, is overexpressed in human renal clear carcinoma (RCC); however, its impact on apoptosis remains unclear. Results revealed that inhibition (SID, a specific inhibitor), knockdown (siRNA), or knockout of Cat L sensitizes human carcinoma cells to anticancer drugs-mediated apoptosis through the downregulation of Bcl-xL and Survivin at the post-translational level. Moreover, combined treatment with SID and sorafenib reduced the tumor growth in a xenograft model. Deletion of Cat L induced Parkin stabilization by increasing DUB3 expression at the transcriptional level. Parkin knockdown significantly prevented SID-induced Bcl-xL downregulation. Conversely, ectopic expression of Parkin suppressed Bcl-xL expression. Furthermore, SID-mediated Parkin upregulation inhibited USP53 deubiquitinase protein expression, leading to the degradation of Survivin expression through its ubiquitination. Parkin directly ubiquitinated Bcl-xL and USP53, but not Survivin. These results demonstrate that inhibition of Cat L enhances anticancer drugs-induced apoptosis through Parkin-mediated ubiquitination of Bcl-xL and USP53. Moreover, the downregulation of USP53 suppressed the expression of Survivin. Therefore, Cat L can be considered a potential candidate molecular target for the treatment of RCC.