Pu Xufeng, Li Li, Chen Zhenhui, Gong Aihua, Lei Jiao, Zhang Lirong, Tsai Hsiang-I
Institute of Medical Imaging and Artificial Intelligence, 212001, Zhenjiang, Jiang Su Province, China.
Department of Cell Biology, School of Medicine, Jiangsu University, 212001, Zhenjiang, Jiang Su Province, China.
J Cancer. 2023 May 15;14(8):1336-1349. doi: 10.7150/jca.83556. eCollection 2023.
Potassium (K) is a vital intracellular cation. In the human body, it regulates membrane potential, electrical excitation, protein synthesis, and cell death. Recent studies revealed that dying cancer cells release potassium into the tumor microenvironment (TME), thereby influencing cell survival-related events. Several investigations reported that potassium channels and high potassium levels influence apoptosis. Increasing extracellular potassium and inhibiting K efflux channels significantly block the apoptotic machinery. However, it is unknown whether a high-potassium environment also affects other types of cell death such as ferroptosis. In the present study, cell counting kit (CCK-8), colony formation ability, and 5-ethynyl-2'-deoxyuridine (EdU) assays demonstrated that a high-potassium environment reverses erastin-induced ferroptosis. RNA sequencing (RNA-Seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analyses indicated that high potassium levels attenuated the unfolded protein response that is characteristic of endoplasmic reticulum (ER) stress. The ER transmembrane proteins PRKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) are recognized as ER stress sensors. Here, the PERK blocker GSK2606414 significantly rescued ferroptosis. The present work also disclosed that the ER-related gene activating transcription factor 3 (ATF3 played a vital role in regulating ferroptosis in a high-potassium environment. The foregoing results revealed the roles of potassium and the TME in cancer cell ferroptosis and provided a potential clinical therapeutic strategy for cancer.
钾（K）是一种重要的细胞内阳离子。在人体中，它调节膜电位、电兴奋、蛋白质合成和细胞死亡。最近的研究表明，垂死的癌细胞会将钾释放到肿瘤微环境（TME）中，从而影响与细胞存活相关的事件。几项研究报告称，钾通道和高钾水平会影响细胞凋亡。增加细胞外钾浓度并抑制钾外流通道可显著阻断凋亡机制。然而，高钾环境是否也会影响其他类型的细胞死亡，如铁死亡，尚不清楚。在本研究中，细胞计数试剂盒（CCK-8）、集落形成能力和5-乙炔基-2'-脱氧尿苷（EdU）检测表明，高钾环境可逆转埃拉司亭诱导的铁死亡。RNA测序（RNA-Seq）以及京都基因与基因组百科全书（KEGG）和基因本体论（GO）分析表明，高钾水平减弱了内质网（ER）应激所特有的未折叠蛋白反应。ER跨膜蛋白蛋白激酶R样内质网激酶（PERK）、肌醇需求酶1α（IRE1α）和活化转录因子6（ATF6）被认为是ER应激传感器。在此，PERK阻断剂GSK2606414显著挽救了铁死亡。本研究还揭示，ER相关基因活化转录因子3（ATF3）在高钾环境下调节铁死亡中起关键作用。上述结果揭示了钾和TME在癌细胞铁死亡中的作用，并为癌症提供了一种潜在的临床治疗策略。
