HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1.-猫眼课题宝

DOI：

10.1016/j.celrep.2023.112945

发表时间：

2023-08

期刊：

Cell reports

影响因子：

8.8

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Zhou Yang;Wei Su;Xiyi Wei;Shuang Qu;Dan Zhao;Jingwan Zhou;Yunjun Wang;Qing Guan;Chao Qin;J. Xiang;Ke Zen;B. Yao

实体瘤对铁性下垂有很强的抵抗力。然而，实体肿瘤中铁下垂抵抗调节的机制仍然不清楚。在这里，我们报告了低氧的肿瘤微环境以缺氧诱导因子1α(HIF-1α)依赖的方式有效地促进实体肿瘤的铁下垂抵抗。低氧诱导因子-2α与促进低氧下肿瘤铁下垂的HIF-2α结合，是低氧诱导铁下垂抵抗的主要驱动因素。在机制上，缺氧诱导因子-1α诱导的乳酸以一种与经典的SLC7A11和FSP1系统平行的pH依赖的方式促进铁下垂抵抗。此外，缺氧诱导因子-1α还可促进重要的谷氨酸转运体SLC1A1的转录，并促进胱氨酸摄取，从而促进对铁性下垂的抵抗。为了支持缺氧在铁性下垂抵抗中的作用，沉默HIF-1α使小鼠实体瘤对铁性下垂诱导剂敏感。综上所述，我们的结果揭示了缺氧导致铁下垂抵抗的机制，并确定了缓解缺氧和诱导铁下垂相结合是治疗实体瘤的一种有前景的治疗策略。

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 ofSLC1A1, 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.

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

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