Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential
Clear cell renal cell carcinoma (ccRCC) poses a significant global health challenge as its incidence continues to rise, resulting in a substantial annual mortality rate. Major clinical challenges to current ccRCC treatments include high drug-resistance rates as well as dose-limiting adverse events;...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
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| Series: | Cancer Treatment and Research Communications |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468294225000024 |
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| Summary: | Clear cell renal cell carcinoma (ccRCC) poses a significant global health challenge as its incidence continues to rise, resulting in a substantial annual mortality rate. Major clinical challenges to current ccRCC treatments include high drug-resistance rates as well as dose-limiting adverse events; underlining the need to identify additional ‘druggable’ targets. TGF-β1, VEGF, and PD-L1 are potential therapeutic targets in ccRCC. This study analyzed their expression in human ccRCC cell lines and patient tumor biopsies. Data obtained from western blotting demonstrated higher levels of TGF-β1 and PD-L1 and lower levels of VEGF in sarcomatoid ccRCC cell lines compared to non-sarcomatoid ccRCC cell lines. In patient samples, TGF-β1 was significantly upregulated in both non-sarcomatoid and sarcomatoid ccRCC tumors. It was demonstrated through two assays (cellular thermal shift assay and a size exclusion assay) that methylseleninic acid (MSA) binds specifically and directly to TGF-β1. MSA treatment significantly downregulated TGF-β1, PD-L1, and VEGF in a dose- and time-dependent manner in both non-sarcomatoid and sarcomatoid ccRCC cell lines. Seleno-L-methionine (SLM) treatment in a nude mouse xenograft model showed a significant tumor growth inhibition and TGF-β1 downregulation at non-toxic doses. These findings suggest that selenium-mediated downregulation of TGF-β1, PD-L1, and VEGF could be a viable therapeutic strategy for ccRCC. |
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| ISSN: | 2468-2942 |