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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| Format: | Article |
| Language: | English |
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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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| author | Aseel O. Rataan Yan Xu Sean M. Geary Yousef Zakharia Eman S. Kamel Youcef M. Rustum Aliasger K. Salem |
| author_facet | Aseel O. Rataan Yan Xu Sean M. Geary Yousef Zakharia Eman S. Kamel Youcef M. Rustum Aliasger K. Salem |
| author_sort | Aseel O. Rataan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-93ee047fa0ac46c788bbba95a2954c8b |
| institution | Kabale University |
| issn | 2468-2942 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cancer Treatment and Research Communications |
| spelling | doaj-art-93ee047fa0ac46c788bbba95a2954c8b2025-02-09T05:00:47ZengElsevierCancer Treatment and Research Communications2468-29422024-01-0142100864Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potentialAseel O. Rataan0Yan Xu1Sean M. Geary2Yousef Zakharia3Eman S. Kamel4Youcef M. Rustum5Aliasger K. Salem6Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA; Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, JordanDepartment of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USADepartment of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, Division of Hematology and Oncology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USADepartment of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Roswell Park Comprehensive Cancer Center, Department of Pharmacology & Therapeutics, Buffalo, NY 14203, USADepartment of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2468294225000024 |
| spellingShingle | Aseel O. Rataan Yan Xu Sean M. Geary Yousef Zakharia Eman S. Kamel Youcef M. Rustum Aliasger K. Salem Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential Cancer Treatment and Research Communications |
| title | Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential |
| title_full | Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential |
| title_fullStr | Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential |
| title_full_unstemmed | Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential |
| title_short | Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential |
| title_sort | targeting transforming growth factor β1 by methylseleninic acid seleno l methionine in clear cell renal cell carcinoma mechanisms and therapeutic potential |
| url | http://www.sciencedirect.com/science/article/pii/S2468294225000024 |
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