Ketamine Induces Ferroptosis of Liver Cancer Cells by Targeting lncRNA PVT1/miR-214-3p/GPX4

Abstract

Background Liver cancer ranks the top four malignant cancer type worldwide, which needs effective and safe treatment. Ferroptosis is a novel form of regulated cell death driven by iron-dependent lipid peroxidation and has been regarded as a promising therapeutic target for cancers. In this work, we aimed to study the effects of anesthetic ketamine on proliferation and ferroptosis of liver cancer. Methods Cell viability and proliferation were detected by cell counting kit 8 (CCK-8), colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assay. Ferroptosis was determined by levels of Fe 2+ , lipid reactive oxygen species (ROS), and malondialdehyde (MDA). RNA levels of lncPVT1, miR-214-3p, and glutathione peroxidase 4 (GPX4) were checked by real-time PCR assay. Clinical liver tumor samples were collected to detect the levels of long noncoding RNA lncPVT1, miR-214-3p, and GPX4, and their correlation was evaluated by Pearson comparison test. Luciferase reporter gene assay and RNA pulldown were conducted to determine the binding between lncPVT1, miR-214-3p, and GPX4 3ʹUTR. Results Ketamine significantly suppressed viability and proliferation of liver cancer cells both in vitro and in vivo, as well as stimulated ferroptosis, along with decreased expression of lncPVT1 and GPX4. LncPVT1 directly interacted with miR-214-3p to impede its role as a sponge of GPX4. Depletion of lncPVT1 accelerated the ferroptosis of live cancer cells, whereas miR-214-3p inhibition and GPX4 overexpression reversed this effect. Ketamine-induced cell growth suppression and ferroptosis were also suppressed by miR-214-3p inhibition and GPX4 overexpression. Conclusion In this work, we determined that ketamine suppressed viability of liver cancer cells and induced ferroptosis and identified the possible regulatory mechanism of lncPVT1/miR-214-3p/GPX4 axis.

Regulation of Ferroptosis by Non-Coding RNAs in Head and Neck Cancers

“…Moreover, higher salivary miR-15a-5p can predict a better prognosis for patients with head and neck cancers treated with intensity-modulated radiation therapy [ 81 ]. Furthermore, miR-214-3p has been proven to interact and bind to the 3ʹUTR of GPX4 in liver cancer cells [ 82 ], and GPX4 is also a direct target of miR-324-3p, which was downregulated in lung adenocarcinoma A549 cells [ 84 ]. In NPC tissues, the expression of miR-324-3p was also reduced and ectopic expression of miR-324-3p inhibited migration and invasion of NPC cells [ 86 ].…”

Regulation of apoptosis, autophagy and ferroptosis by non‑coding RNAs in metastatic non‑small cell lung cancer (Review)

“…Additionally, H19 may promote cancer progression and suppress ferroptosis by regulating the miR-106b-5p/ACSL4 axis ( 102 ). PVT1 can also regulate ferroptosis via miR-214-mediated TFR1 and TP53 expression ( 104 ); notably, GPX4 has also been demonstrated to be a target of miR-214-3p. Notably, ketamine has been reported to inhibit the proliferation of liver cancer cells in vitro and in vivo by inducing ferroptosis via the lncRNA PVT1/miR-214-3p/GPX4 pathway ( 104 ).…”

“…PVT1 can also regulate ferroptosis via miR-214-mediated TFR1 and TP53 expression ( 104 ); notably, GPX4 has also been demonstrated to be a target of miR-214-3p. Notably, ketamine has been reported to inhibit the proliferation of liver cancer cells in vitro and in vivo by inducing ferroptosis via the lncRNA PVT1/miR-214-3p/GPX4 pathway ( 104 ). lncRNA ZFAS1 can also induce ferroptosis by functioning as a ceRNA through the miR-150-5p/SLC38A1 axis ( 105 ).…”

Non-coding RNAs and ferroptosis: potential implications for cancer therapy

“… lncRNA Role in ferroptosis Mechanism of action Reference P53RRA (LINC00472) Induces ferroptosis in lung cancer Downregulates SCL7A11 [ 38 ] MT1DP Induces ferroptosis in NSCLC Stabilizes miR-365a-3p, downregulates NRF2 [ 113 ] GABPB1-AS1 Induces ferroptosis in HCC Inhibits GABPB1 translation, downregulates GABPB1 and PRDX5 [ 112 ] LINC00618 Induces ferroptosis in leukemias Downregulates SLC7A11 via attenuation of LSH expression [ 37 ] LINC00336 Inhibits ferroptosis in lung cancer Stabilized by ELAVL1 and LSH. Sponges miRNA6852, upregulates CBS [ 114 ] NEAT1 Inhibits ferroptosis in NSCLC Downregulates ACSL4 expression [ 56 ] H19 Inhibits ferroptosis in breast cancer Inhibits production of lipid ROS and induces production of GSH [ 175 ] lncPVT1 Inhibits ferroptosis in HCC Sponges miR-214-3p, upregulates GPX4 [ 29 ] OIP5-AS1 Inhibits ferroptosis in prostate cancer Sponges miR-128-3p, upregulates SLC7A11 expression [ 39 ] RP11-89 Inhibits ferroptosis in bladder cancer Sponges miR-129-5p, upregulates PROM2 which induces iron export [ 176 ] MEG8 Inhibits ferroptosis in benign hemangioma Sponged by miR-497-5p. Upregulates SLC7A11 and GPX4 expression [ 177 ] …”