Thiouracil and triazole conjugate induces autophagy through the downregulation of Wnt/β‐catenin signaling pathway in human breast cancer cells
Autophagy is vital for maintaining cellular homeostasis by breaking down unnecessary organelles and proteins within cells. Its activity varies abnormally in several diseases, including cancer, making it a potential target for therapeutic strategies. The Wnt/β‐catenin signaling pathway significantly...
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| Veröffentlicht in: | IUBMB life 2024-12, Vol.76 (12), p.1377-1391 |
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| creator | Yoon, Bada Basappa, Basappa Basappa, Shreeja Nagaraju, Omantheswara Madegowda, Mahendra Rangappa, K. S. Sethi, Gautam Ahn, Kwang Seok |
| description | Autophagy is vital for maintaining cellular homeostasis by breaking down unnecessary organelles and proteins within cells. Its activity varies abnormally in several diseases, including cancer, making it a potential target for therapeutic strategies. The Wnt/β‐catenin signaling pathway significantly impacts cancer by stabilizing β‐catenin protein and promoting the transcription of its target genes. Therefore, we aimed to identify candidate substances targeting this signaling pathway. We designed and tested a thiouracil conjugate, discovering that TTP‐8 had anti‐tumor effects on human breast cancer cell lines MCF‐7 and MDA‐MB231. Our findings showed that TTP‐8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP‐8 might induce autophagy. Further analysis confirmed an increase in autophagy‐related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP‐8 was even more pronounced in MCF‐7 and MDA‐MB231 cells transfected with β‐catenin siRNA. Thus, our research supports the idea that the Wnt/β‐catenin signaling pathway influences the regulation of autophagy‐related proteins, thereby inducing autophagy. This suggests that TTP‐8 could serve as a novel agent for treating breast cancer. |
| doi_str_mv | 10.1002/iub.2917 |
| format | Article |
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Our findings showed that TTP‐8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP‐8 might induce autophagy. Further analysis confirmed an increase in autophagy‐related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP‐8 was even more pronounced in MCF‐7 and MDA‐MB231 cells transfected with β‐catenin siRNA. Thus, our research supports the idea that the Wnt/β‐catenin signaling pathway influences the regulation of autophagy‐related proteins, thereby inducing autophagy. 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Our findings showed that TTP‐8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP‐8 might induce autophagy. Further analysis confirmed an increase in autophagy‐related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP‐8 was even more pronounced in MCF‐7 and MDA‐MB231 cells transfected with β‐catenin siRNA. Thus, our research supports the idea that the Wnt/β‐catenin signaling pathway influences the regulation of autophagy‐related proteins, thereby inducing autophagy. This suggests that TTP‐8 could serve as a novel agent for treating breast cancer.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Catenin</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Confocal microscopy</subject><subject>Down-Regulation - drug effects</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Organelles</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>siRNA</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><subject>TTP‐8</subject><subject>Tumor cell lines</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - drug effects</subject><subject>Wnt/β‐catenin pathway</subject><issn>1521-6543</issn><issn>1521-6551</issn><issn>1521-6551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kUtuFDEQhlsIREJA4gTIEhs2nfjVrxWCKJBIkdgkYmlVu93dHnnswY-MhhVHCFfhIBwiJ4knCcNDwpuy5M-f_qoqipcEHxKM6ZFO_SHtSPOo2CcVJWVdVeTx7s7ZXvEshAXOp8Hd02KPdbRqKOH7xfeLWbvkQWqDwA4oeg1fnVFIOrtIE0SFtB2SVAFBim41w7RBcfYuTXOuCg1ubb2akoGonUVuRJ9tPPr54-bbtcy_rbYo6MmC0XZCK4jzGjZZiea0BIt6ryBEJMFK5ZFUxoTnxZMRTFAvHupBcfnh5OL4tDz_9PHs-N15KRnDTUnGoYYG15i2TZcbk7yHmo6U1wNuuepHTDnluCcSK9YyTlnFoelJ2_Q8sxU7KN7ee1epX6pBKhs9GLHyegl-Ixxo8feL1bOY3JUgpGoxa-psePNg8O5LUiGKpQ7bHsAql4JgJIdrc0Sc0df_oIs89TyVLcUIaTGuut9C6V0IXo27NASL7aJFXrTYLjqjr_5MvwN_bTYD5T2w1kZt_isSZ5fv74S3UvG2EA</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Yoon, Bada</creator><creator>Basappa, Basappa</creator><creator>Basappa, Shreeja</creator><creator>Nagaraju, Omantheswara</creator><creator>Madegowda, Mahendra</creator><creator>Rangappa, K. 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Therefore, we aimed to identify candidate substances targeting this signaling pathway. We designed and tested a thiouracil conjugate, discovering that TTP‐8 had anti‐tumor effects on human breast cancer cell lines MCF‐7 and MDA‐MB231. Our findings showed that TTP‐8 upregulated the expression of LC3 protein, a marker of autophagy in breast cancer cells, suggesting that TTP‐8 might induce autophagy. Further analysis confirmed an increase in autophagy‐related proteins, with consistent results obtained from flow cytometry and confocal microscopy. Interestingly, the induction of LC3 expression by TTP‐8 was even more pronounced in MCF‐7 and MDA‐MB231 cells transfected with β‐catenin siRNA. Thus, our research supports the idea that the Wnt/β‐catenin signaling pathway influences the regulation of autophagy‐related proteins, thereby inducing autophagy. 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| subjects | Antineoplastic Agents - pharmacology Autophagy Autophagy - drug effects beta Catenin - genetics beta Catenin - metabolism Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Catenin Cell Line, Tumor Cell Proliferation - drug effects Confocal microscopy Down-Regulation - drug effects Female Flow cytometry Gene Expression Regulation, Neoplastic - drug effects Homeostasis Humans MCF-7 Cells Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Organelles Proteins Signal transduction siRNA Triazoles - chemistry Triazoles - pharmacology TTP‐8 Tumor cell lines Wnt protein Wnt Signaling Pathway - drug effects Wnt/β‐catenin pathway |
| title | Thiouracil and triazole conjugate induces autophagy through the downregulation of Wnt/β‐catenin signaling pathway in human breast cancer cells |
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