dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers
Abstract Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-24706-4 |
| _version_ | 1811304506277756928 |
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| author | Dae-Ho Kim Jin-Sook Kim Chang-Soo Mok En-Hyung Chang Jiwon Choi Junsub Lim Chul-Ho Kim Ah-Reum Park Yu-Jeong Bae Bong-Seong Koo Hyeon-Cheol Lee |
| author_facet | Dae-Ho Kim Jin-Sook Kim Chang-Soo Mok En-Hyung Chang Jiwon Choi Junsub Lim Chul-Ho Kim Ah-Reum Park Yu-Jeong Bae Bong-Seong Koo Hyeon-Cheol Lee |
| author_sort | Dae-Ho Kim |
| collection | DOAJ |
| description | Abstract Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing nucleotide imbalance and apoptosis in triple negative breast cancer cells (TNBC), by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as tricarboxylic acid cycle intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5′ nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability. |
| first_indexed | 2024-04-13T08:08:21Z |
| format | Article |
| id | doaj.art-ca8568f3392a40a7a446857a66c224e7 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T08:08:21Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ca8568f3392a40a7a446857a66c224e72022-12-22T02:55:06ZengNature PortfolioScientific Reports2045-23222022-11-0112112210.1038/s41598-022-24706-4dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancersDae-Ho Kim0Jin-Sook Kim1Chang-Soo Mok2En-Hyung Chang3Jiwon Choi4Junsub Lim5Chul-Ho Kim6Ah-Reum Park7Yu-Jeong Bae8Bong-Seong Koo9Hyeon-Cheol Lee10Research Center, BPgene Co, LtdResearch Center, BPgene Co, LtdResearch Center, BPgene Co, LtdResearch Center, BPgene Co, LtdResearch Center, BPgene Co, LtdResearch Center, BPgene Co, LtdDepartment of Otolaryngology, Ajou University School of MedicineForBioKorea Co., LtdForBioKorea Co., LtdResearch Center, BPgene Co, LtdResearch Center, BPgene Co, LtdAbstract Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing nucleotide imbalance and apoptosis in triple negative breast cancer cells (TNBC), by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as tricarboxylic acid cycle intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5′ nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability.https://doi.org/10.1038/s41598-022-24706-4 |
| spellingShingle | Dae-Ho Kim Jin-Sook Kim Chang-Soo Mok En-Hyung Chang Jiwon Choi Junsub Lim Chul-Ho Kim Ah-Reum Park Yu-Jeong Bae Bong-Seong Koo Hyeon-Cheol Lee dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers Scientific Reports |
| title | dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers |
| title_full | dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers |
| title_fullStr | dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers |
| title_full_unstemmed | dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers |
| title_short | dTMP imbalance through thymidylate 5′-phosphohydrolase activity induces apoptosis in triple-negative breast cancers |
| title_sort | dtmp imbalance through thymidylate 5 phosphohydrolase activity induces apoptosis in triple negative breast cancers |
| url | https://doi.org/10.1038/s41598-022-24706-4 |
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