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Radiosensitizing effect of a novel CTSS inhibitor by enhancing BRCA1 protein stability in triple-negative breast cancer cells.
Choi, Eun; Jeon, Kyung-Hwa; Lee, Hanhee; Mun, Gil-Im; Kim, Jeong-Ahn; Shin, Jae-Ho; Kwon, Youngjoo; Na, Younghwa; Lee, Yun-Sil.
Affiliation
  • Choi E; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Jeon KH; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Lee H; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Mun GI; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Kim JA; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Shin JH; College of Pharmacy, CHA University, Pocheon, Korea.
  • Kwon Y; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
  • Na Y; College of Pharmacy, CHA University, Pocheon, Korea.
  • Lee YS; Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Women's University, Seoul, Korea.
Cancer Sci ; 115(6): 2036-2048, 2024 Jun.
Article in En | MEDLINE | ID: mdl-38613358
ABSTRACT
Triple-negative breast cancer (TNBC) patients harboring wild-type breast cancer susceptibility gene 1 (BRCA1) account for most TNBC patients but lack adequate targeted therapeutic options. Although radiotherapy (RT) is the primary treatment modality for TNBC patients, radioresistance is one of the major challenges. RT-induced increase in cathepsin S (CTSS) causes radioresistance through suppressing BRCA1-mediated apoptosis of tumor cells, which was induced by CTSS-mediated degradation of BRCA1. Targeting CTSS may provide a novel therapeutic opportunity for TNBC patients. Publicly available data and human tissue microarray slides were analyzed to investigate the relationship between CTSS and BRCA1 in breast cancer patients. A CTSS enzyme assay and in silico docking analysis were conducted to identify a novel CTSS inhibitor. RO5461111 was used first to confirm the concept of targeting CTSS for radiosensitizing effects. The MDA-MB-231 TNBC cell line was used for in vitro and in vivo assays. Western blotting, promoter assay, cell death assay, clonogenic survival assay, and immunohistochemistry staining were conducted to evaluate novel CTSS inhibitors. CTSS inhibitors were further evaluated for their additional benefit of inhibiting cell migration. A novel CTSS inhibitor, TS-24, increased BRCA1 protein levels and showed radiosensitization in TNBC cells with wild-type BRCA1 and in vivo in a TNBC xenograft mouse model. These effects were attributed by BRCA1-mediated apoptosis facilitated by TS-24. Furthermore, TS-24 demonstrated the additional effect of inhibiting cell migration. Our study suggests that employing CTSS inhibitors for the functional restoration of BRCA1 to enhance RT-induced apoptosis may provide a novel therapeutic opportunity for TNBC patients harboring wild-type BRCA1.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Radiation-Sensitizing Agents / Apoptosis / BRCA1 Protein / Triple Negative Breast Neoplasms Limits: Animals / Female / Humans Language: En Journal: Cancer Sci Year: 2024 Document type: Article Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Radiation-Sensitizing Agents / Apoptosis / BRCA1 Protein / Triple Negative Breast Neoplasms Limits: Animals / Female / Humans Language: En Journal: Cancer Sci Year: 2024 Document type: Article Country of publication: United kingdom