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HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1

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Title: HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1
Authors: Zhou Yang, Wei Su, Xiyi Wei, Shuang Qu, Dan Zhao, Jingwan Zhou, Yunjun Wang, Qing Guan, Chao Qin, Jun Xiang, Ke Zen, Bing Yao
Source: Cell Reports, Vol 42, Iss 8, Pp 112945- (2023)
Publisher Information: Elsevier, 2023.
Publication Year: 2023
Collection: LCC:Biology (General)
Subject Terms: CP: Cancer, CP: Metabolism, Biology (General), QH301-705.5
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2211-1247
Relation: http://www.sciencedirect.com/science/article/pii/S2211124723009567; https://doaj.org/toc/2211-1247
DOI: 10.1016/j.celrep.2023.112945
Access URL: https://doaj.org/article/6667ba1d7c184aaebfaf452b798d07bc
Accession Number: edsdoj.6667ba1d7c184aaebfaf452b798d07bc
Database: Directory of Open Access Journals
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  Data: HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1
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  Data: <searchLink fieldCode="AR" term="%22Zhou+Yang%22">Zhou Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Wei+Su%22">Wei Su</searchLink><br /><searchLink fieldCode="AR" term="%22Xiyi+Wei%22">Xiyi Wei</searchLink><br /><searchLink fieldCode="AR" term="%22Shuang+Qu%22">Shuang Qu</searchLink><br /><searchLink fieldCode="AR" term="%22Dan+Zhao%22">Dan Zhao</searchLink><br /><searchLink fieldCode="AR" term="%22Jingwan+Zhou%22">Jingwan Zhou</searchLink><br /><searchLink fieldCode="AR" term="%22Yunjun+Wang%22">Yunjun Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Qing+Guan%22">Qing Guan</searchLink><br /><searchLink fieldCode="AR" term="%22Chao+Qin%22">Chao Qin</searchLink><br /><searchLink fieldCode="AR" term="%22Jun+Xiang%22">Jun Xiang</searchLink><br /><searchLink fieldCode="AR" term="%22Ke+Zen%22">Ke Zen</searchLink><br /><searchLink fieldCode="AR" term="%22Bing+Yao%22">Bing Yao</searchLink>
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  Data: Cell Reports, Vol 42, Iss 8, Pp 112945- (2023)
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  Data: 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.
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