HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1
Zhou Yang,
Wei Su,
Xiyi Wei,
Shuang Qu,
Dan Zhao,
Jingwan Zhou,
Yunjun Wang,
Qing Guan,
Chao Qin,
Jun Xiang,
Ke Zen,
Bing Yao
Affiliations
Zhou Yang
National 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, China
Wei Su
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
Xiyi Wei
The State Key Lab of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Shuang Qu
School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
Dan Zhao
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Jingwan Zhou
National Experimental Teaching Center of Basic Medical Science, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
Yunjun Wang
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Qing Guan
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Chao Qin
The State Key Lab of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding author
Jun Xiang
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding author
Ke Zen
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China; Corresponding author
Bing Yao
National 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 author
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.
