HIF-1[alpha] inhibits ferroptosis and promotes malignant progression in non-small cell lung cancer by activating the Hippo-YAP signalling pathway

• Published in: Oncology letters 2023-03, Vol.25 (3), p.1
• Main Authors: Zheng, Senzhong, Mo, Ji, Zhang, Jing, Chen, Yang
• Format: Article
• Language: English
• Subjects: Apoptosis; B cells; Development and progression; Lung cancer, Non-small cell; Lung cancer, Small cell; RNA; Scientific equipment and supplies industry
• ISSN: 1792-1074
• DOI: 10.3892/ol.2023.13676

Ferroptosis and hypoxia-inducible factor 1[alpha] (HIF-1[alpha]) have critical roles in human tumors. The aim of the present study was to investigate the associations between ferroptosis, HIF-1[alpha] and cell growth in non-small cell lung cancer (NSCLC) cells. The lung cancer cell lines SW900 and A549 were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to detect the expression of HIF-1[alpha]. Cell Counting Kit-8, flow cytometry and Transwell migration assays were used to measure cell viability, apoptosis and invasion, respectively. The production of reactive oxygen species (ROS) and levels of malondialdehyde (MDA), gluta-thione (GSH) and ferrous ion ([Fe.sup.2+]) were determined using detection kits. The expression levels of glutathione peroxidase 4 (GPX4) and Yes-associated protein 1 (YAP1) were detected using RT-qPCR and western blotting. The results showed that the expression of HIF-1[alpha] was significantly upregulated in NSCLC cells compared with normal human bronchial epithelial cells. Small interfering RNA specific to HIF-1[alpha] (si-HIF-1[alpha]) significantly decreased the proliferation and invasion of NSCLC cells and increased their apoptosis. si-HIF-1[alpha] also increased the levels of ROS, MDA and [Fe.sup.2+] but decreased GSH and GPX4 levels in A549 cells. Additionally, si-HIF-1[alpha] increased phosphorylated (p-)YAP1 levels, suppressed GPX4 and YAP1 expression, and attenuated the YAP1 overexpression-induced changes in YAP1, p-YAP1 and GPX4 levels and cell viability. The ferroptosis antagonist ferrostatin-1 partially attenuated the effects of si-HIF-1[alpha] on the NSCLC cells, while the ferroptosis agonist erastin further inhibited NSCLC growth by blocking HIF-1[alpha] expression. In conclusion, the silencing of HIF-1[alpha] induces ferroptosis by suppressing Hippo-YAP pathway activation in NSCLC cells. The present study provides novel insights into the malignant progression of NSCLC and suggests that HIF-1[alpha] is an effective target for the treatment of NSCLC. Key words: non-small cell lung cancer, hypoxia-inducible factor 1[alpha], ferroptosis, oxidative stress, Hippo-YAP pathway