التفاصيل البيبلوغرافية
| العنوان: |
HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1. |
| المؤلفون: |
Yang, Zhou, Su, Wei, Wei, Xiyi, Qu, Shuang, Zhao, Dan, Zhou, Jingwan, Wang, Yunjun, Guan, Qing, Qin, Chao, Xiang, Jun, Zen, Ke, Yao, Bing |
| المصدر: |
Cell Reports; Aug2023, Vol. 42 Issue 8, pN.PAG-N.PAG, 1p |
| مستخلص: |
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. [Display omitted] • HIF-1α, but not HIF-2α, is the main driver of ferroptosis resistance under hypoxia • HIF-1α-induced lactate drives ferroptosis resistance in a pH-dependent manner • HIF-1α promotes cystine uptake by upregulating glutamate transporter SLC1A1 • Hypoxia relief sensitizes solid tumors to ferroptosis inducers Yang et al. demonstrate the mechanisms by which tumor cell ferroptosis is modulated under hypoxia. HIF-1α serves as the main driver to promote ferroptosis resistance in tumor cells under hypoxia through two independent pathways: the generation of a lactate-induced acidic environment and the activity of the glutamate transporter SLC1A1. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
