Deng Xuan, Chang Lu, Tang Lingyu, Jiang Haoqin, Xu Xiao, Zhang Xinju, Chen Jian, Dong Liu, Xu Qianqian, Cao Ruoshui, Xiang Jianbin, Guan Ming
Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China.
Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Cell Death Dis. 2025 Feb 1;16(1):62. doi: 10.1038/s41419-025-07374-w.
Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.
获得性耐药对铂类癌症治疗的有效性构成了重大障碍。作为最丰富的抗氧化剂，谷胱甘肽（GSH）通过清除铂诱导产生的过量活性氧（ROS），使癌细胞得以存活并产生化疗耐药性。针对GSH合成的治疗策略已经开发出来，然而，在预防癌症进展方面未能产生理想效果。因此，揭示GSH代谢重编程的机制可能有助于开发额外的治疗策略，以克服或延缓耐药性。在这里，我们发现与亲本细胞相比，铂耐药的结直肠癌（CRC）和卵巢癌细胞中长链非编码RNA（lncRNA）GDIL（GSH降解抑制lncRNA）上调。GDIL在耐药CRC中的高表达与较差的生存率和化疗低敏感性相关。我们证明，GDIL提高了GSH水平，并增强了对铂诱导的ROS的清除。代谢组学和代谢通量分析进一步揭示，GDIL通过抑制GSH降解促进GSH积累。这是由于CHAC1的下调，CHAC1是一种特异性降解细胞内GSH的酶。从机制上讲，GDIL与核蛋白XRN2结合并将其重新定位到细胞质中，在那里GDIL进一步作为XRN2的支架，以识别和降解CHAC1 mRNA。用选择性反义寡核苷酸抑制GDIL，可恢复铂耐药细胞系的药物敏感性，并延缓细胞系和患者来源异种移植瘤中的耐药性。因此，lncRNA GDIL是促进GSH降解和增强铂类治疗的新靶点。
