Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, 04037-003, Brazil.
Institute of Biomedical Science, University of São Paulo (USP), São Paulo, 04037-003, Brazil.
Cell Death Dis. 2022 Jul 8;13(7):591. doi: 10.1038/s41419-022-05044-9.
Glioblastoma patients have a poor prognosis mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its protective role in the transcription of genes involved in cellular detoxification and prevention of cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death in glioma is still poorly understood. Therefore, in this study, we analyzed the role of NRF2 in ferroptosis modulation in glioblastoma cells. Two human glioblastoma cell lines (U251MG and T98G) were examined after treatment with TMZ, ferroptosis inducers (Erastin, RSL3), and ferroptosis inhibitor (Ferrostatin-1). Our results demonstrated that T98G was more resistant to chemotherapy compared to U251MG and showed elevated levels of NRF2 expression. Interestingly, T98G revealed higher sensitivity to ferroptosis, and significant GSH depletion upon system xc blockage. NRF2 silencing in T98G cells (T98G-shNRF2) significantly reduced the viability upon TMZ treatment. On the other hand, T98G-shNRF2 was resistant to ferroptosis and reverted intracellular GSH levels, indicating that NRF2 plays a key role in ferroptosis induction through GSH modulation. Moreover, silencing of ABCC1, a well-known NRF2 target that diminishes GSH levels, has demonstrated a similar collateral sensitivity. T98G-siABCC1 cells were more sensitive to TMZ and resistant to Erastin. Furthermore, we found that NRF2 positively correlates with ABCC1 expression in tumor tissues of glioma patients, which can be associated with tumor aggressiveness, drug resistance, and poor overall survival. Altogether, our data indicate that high levels of NRF2 result in collateral sensitivity on glioblastoma via the expression of its pro-ferroptotic target ABCC1, which contributes to GSH depletion when the system xc is blocked by Erastin. Thus, ferroptosis induction could be an important therapeutic strategy to reverse drug resistance in gliomas with high NRF2 and ABCC1 expression.
胶质母细胞瘤患者预后较差，主要是由于替莫唑胺（TMZ）耐药。NRF2 是一种重要的转录因子，由于其在参与细胞解毒和防止细胞死亡过程的基因转录中的保护作用，与化疗耐药有关，例如铁死亡。然而，NRF2 与胶质瘤中铁依赖性细胞死亡之间的关系仍知之甚少。因此，在这项研究中，我们分析了 NRF2 在胶质母细胞瘤细胞中铁死亡调节中的作用。在用 TMZ、铁死亡诱导剂（Erastin、RSL3）和铁死亡抑制剂（Ferrostatin-1）处理后，检查了两种人胶质母细胞瘤细胞系（U251MG 和 T98G）。我们的结果表明，与 U251MG 相比，T98G 对化疗的耐药性更高，并且表现出 NRF2 表达水平升高。有趣的是，T98G 对铁死亡的敏感性更高，并且在系统 xc 阻断时 GSH 耗竭明显。在 T98G 细胞中沉默 NRF2（T98G-shNRF2）会显著降低 TMZ 处理后的活力。另一方面，T98G-shNRF2 对铁死亡具有抗性，并恢复了细胞内 GSH 水平，表明 NRF2 通过 GSH 调节在铁死亡诱导中起关键作用。此外，沉默 NRF2 的众所周知的靶点 ABCC1（降低 GSH 水平）也表现出类似的协同敏感性。T98G-siABCC1 细胞对 TMZ 更敏感，对 Erastin 有抗性。此外，我们发现 NRF2 与胶质母细胞瘤患者肿瘤组织中 ABCC1 的表达呈正相关，这与肿瘤侵袭性、耐药性和总体生存不良有关。总的来说，我们的数据表明，高水平的 NRF2 通过表达其促铁死亡靶标 ABCC1 导致胶质母细胞瘤的协同敏感性，当系统 xc 被 Erastin 阻断时，导致 GSH 耗竭。因此，铁死亡诱导可能是一种重要的治疗策略，可以逆转具有高 NRF2 和 ABCC1 表达的胶质母细胞瘤的耐药性。
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