Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators
Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate...
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/2/468 |
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| author | Yuze Wang Toshiaki Ohara Yuehua Chen Yusuke Hamada Chunning Li Masayoshi Fujisawa Teizo Yoshimura Akihiro Matsukawa |
| author_facet | Yuze Wang Toshiaki Ohara Yuehua Chen Yusuke Hamada Chunning Li Masayoshi Fujisawa Teizo Yoshimura Akihiro Matsukawa |
| author_sort | Yuze Wang |
| collection | DOAJ |
| description | Excess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators. |
| first_indexed | 2024-03-09T13:17:20Z |
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| language | English |
| last_indexed | 2024-03-09T13:17:20Z |
| publishDate | 2023-01-01 |
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| series | Cancers |
| spelling | doaj.art-4ab128025b4641d790f93d477fae144c2023-11-30T21:34:18ZengMDPI AGCancers2072-66942023-01-0115246810.3390/cancers15020468Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron ChelatorsYuze Wang0Toshiaki Ohara1Yuehua Chen2Yusuke Hamada3Chunning Li4Masayoshi Fujisawa5Teizo Yoshimura6Akihiro Matsukawa7Department of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pathology and Experimental Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanExcess iron is known to be a risk factor of carcinogenesis. Although iron chelators show anti-cancer effects, they have not been used successfully to treat cancer patients. Triple-negative breast cancer (TNBC) is a disease with poor prognosis without effective treatments. Thus, we aimed to evaluate a possibility of iron chelators as a therapy for TNBC. Deferasirox (DFX), an iron chelator, suppressed the growth of 4T1 murine TNBC cell line cells in vitro and in vivo. Lung metastasis was further significantly reduced, leading to the hypothesis that iron metabolism between metastatic and non-metastatic cells may be different. An analysis of existing database demonstrated that the expression of iron-uptake genes was significantly suppressed in TNBC cells that metastasized to lymph nodes or lungs compared to those in primary tumors. A highly metastatic clone of the murine 4T1 TNBC cells (4T1-HM) did not proliferate well under iron-rich or iron-depleted conditions by iron chelators compared to a low-metastatic clone (4T1-LM). Bulk RNA-seq analysis of RNA from 4T1-HM and 4T1-LM cells suggested that the PI3K-AKT pathway might be responsible for this difference. Indeed, DFX suppressed the proliferation via the AKT-mTOR pathway in 4T1-HM and the human MDA-MB-231 cells, a human mesenchymal-like TNBC cell line. DFX also suppressed the growth of 4T1-HM tumors in comparison to 4T1-LM tumors, and reduced lung metastases after surgical resection of primary 4T1 tumors. These results indicated, for the first time, that highly metastatic TNBC cells have limited iron metabolism, and they can be more effectively targeted by iron chelators.https://www.mdpi.com/2072-6694/15/2/468triple-negative breast canceriron metabolismiron chelatorphosphoinositide-3-kinase-protein kinaseheterogeneitymetastasis |
| spellingShingle | Yuze Wang Toshiaki Ohara Yuehua Chen Yusuke Hamada Chunning Li Masayoshi Fujisawa Teizo Yoshimura Akihiro Matsukawa Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators Cancers triple-negative breast cancer iron metabolism iron chelator phosphoinositide-3-kinase-protein kinase heterogeneity metastasis |
| title | Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators |
| title_full | Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators |
| title_fullStr | Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators |
| title_full_unstemmed | Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators |
| title_short | Highly Metastatic Subpopulation of TNBC Cells Has Limited Iron Metabolism and Is a Target of Iron Chelators |
| title_sort | highly metastatic subpopulation of tnbc cells has limited iron metabolism and is a target of iron chelators |
| topic | triple-negative breast cancer iron metabolism iron chelator phosphoinositide-3-kinase-protein kinase heterogeneity metastasis |
| url | https://www.mdpi.com/2072-6694/15/2/468 |
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