HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1
Summary: Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-indu...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723009567 |
| _version_ | 1797731088814047232 |
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| author | Zhou Yang Wei Su Xiyi Wei Shuang Qu Dan Zhao Jingwan Zhou Yunjun Wang Qing Guan Chao Qin Jun Xiang Ke Zen Bing Yao |
| author_facet | Zhou Yang Wei Su Xiyi Wei Shuang Qu Dan Zhao Jingwan Zhou Yunjun Wang Qing Guan Chao Qin Jun Xiang Ke Zen Bing Yao |
| author_sort | Zhou Yang |
| collection | DOAJ |
| description | Summary: Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors. |
| first_indexed | 2024-03-12T11:53:43Z |
| format | Article |
| id | doaj.art-6667ba1d7c184aaebfaf452b798d07bc |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:43Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6667ba1d7c184aaebfaf452b798d07bc2023-08-31T05:02:16ZengElsevierCell Reports2211-12472023-08-01428112945HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1Zhou Yang0Wei Su1Xiyi Wei2Shuang Qu3Dan Zhao4Jingwan Zhou5Yunjun Wang6Qing Guan7Chao Qin8Jun Xiang9Ke Zen10Bing Yao11National Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaThe State Key Lab of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing, ChinaDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaNational Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, ChinaDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaThe State Key Lab of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding authorDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding authorState Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China; Corresponding authorNational Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Corresponding authorSummary: Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.http://www.sciencedirect.com/science/article/pii/S2211124723009567CP: CancerCP: Metabolism |
| spellingShingle | Zhou Yang Wei Su Xiyi Wei Shuang Qu Dan Zhao Jingwan Zhou Yunjun Wang Qing Guan Chao Qin Jun Xiang Ke Zen Bing Yao HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 Cell Reports CP: Cancer CP: Metabolism |
| title | HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 |
| title_full | HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 |
| title_fullStr | HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 |
| title_full_unstemmed | HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 |
| title_short | HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1 |
| title_sort | hif 1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating slc1a1 |
| topic | CP: Cancer CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723009567 |
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