Knockdown of SLC39A14 Inhibits Glioma Progression by Promoting Erastin-induced Ferroptosis SLC39A14 Knockdown Inhibits Glioma Progression

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2023 Nov 18

PMID 37978473

Authors

Yunwen Zhang

Xinghai Wu

Jiyong Zhu

Ruibin Lu

Yian Ouyang

Affiliations

Soon will be listed here.

Abstract

Background: Ferroptosis is a newly classified form of regulated cell death with implications in various tumor progression pathways. However, the roles and mechanisms of ferroptosis-related genes in glioma remain unclear.

Methods: Bioinformatics analysis was employed to identify differentially expressed ferroptosis-related genes in glioma. The expression levels of hub genes were assessed using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). To explore the role of SLC39A14 in glioma, a series of in vitro assays were conducted, including cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, wound healing, and Transwell assays. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the levels of indicators associated with ferroptosis. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were performed to illustrate the clinicopathological features of the mouse transplantation tumor model. Additionally, Western blot analysis was used to assess the expression of the cGMP-PKG pathway-related proteins.

Results: Seven ferroptosis-related hub genes, namely SLC39A14, WWTR1, STEAP3, NOTCH2, IREB2, HIF1A, and FANCD2, were identified, all of which were highly expressed in glioma. Knockdown of SLC39A14 inhibited glioma cell proliferation, migration, and invasion, while promoting apoptosis. Moreover, SLC39A14 knockdown also facilitated erastin-induced ferroptosis, leading to the suppression of mouse transplantation tumor growth. Mechanistically, SLC39A14 knockdown inhibited the cGMP-PKG signaling pathway activation.

Conclusion: Silencing SLC39A14 inhibits ferroptosis and tumor progression, potentially involving the regulation of the cGMP-PKG signaling pathway.

Citing Articles

Mesenchymal stem cell-derived extracellular vesicles attenuate ferroptosis in aged hepatic ischemia/reperfusion injury by transferring miR-1275.

Gong Y, You Q, Yuan X, Zeng F, Zhang F, Xiao J Redox Biol. 2025; 81:103556.

PMID: 39986119 PMC: 11893313. DOI: 10.1016/j.redox.2025.103556.

Roles and therapeutic potential of the SLC family in prostate cancer-literature review.

Fu Y, Chen J, Zhu X, Ding M, Wang H, Fu S BMC Urol. 2025; 25(1):32.

PMID: 39966814 PMC: 11837367. DOI: 10.1186/s12894-025-01714-w.

Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq.

Desterke C, Fu Y, Bonifacio-Mundaca J, Monge C, Pineau P, Mata-Garrido J Antioxidants (Basel). 2025; 14(1).

PMID: 39857430 PMC: 11761645. DOI: 10.3390/antiox14010096.

Ferroptosis in glioma therapy: advancements in sensitizing strategies and the complex tumor-promoting roles.

Kim S, Tang M, Lu T, Chih S, Li W Brain Res. 2024; 1840:149045.

PMID: 38821335 PMC: 11323215. DOI: 10.1016/j.brainres.2024.149045.

Overcoming challenges in glioblastoma treatment: targeting infiltrating cancer cells and harnessing the tumor microenvironment.

Chiariello M, Inzalaco G, Barone V, Gherardini L Front Cell Neurosci. 2024; 17:1327621.

PMID: 38188666 PMC: 10767996. DOI: 10.3389/fncel.2023.1327621.

References

Aydemir T, Cousins R . The Multiple Faces of the Metal Transporter ZIP14 (SLC39A14). J Nutr. 2018; 148(2):174-184. PMC: 6251594. DOI: 10.1093/jn/nxx041. View

Charles N, Ozawa T, Squatrito M, Bleau A, Brennan C, Hambardzumyan D . Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 2010; 6(2):141-52. PMC: 3818090. DOI: 10.1016/j.stem.2010.01.001. View

Yang W, Huang Z, Wu J, Ding C, Murphy S, Chi J . A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Mol Cancer Res. 2019; 18(1):79-90. PMC: 6942206. DOI: 10.1158/1541-7786.MCR-19-0691. View

Taylor K, Morgan H, Johnson A, Nicholson R . Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett. 2005; 579(2):427-32. DOI: 10.1016/j.febslet.2004.12.006. View

Koppula P, Zhuang L, Gan B . Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2020; 12(8):599-620. PMC: 8310547. DOI: 10.1007/s13238-020-00789-5. View

Lv Y, Wang X, Li X, Xu G, Bai Y, Wu J . Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway. PLoS Biol. 2020; 18(11):e3000872. PMC: 7688141. DOI: 10.1371/journal.pbio.3000872. View

Ding H, Chen S, Pan X, Dai X, Pan G, Li Z . Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis. J Cachexia Sarcopenia Muscle. 2021; 12(3):746-768. PMC: 8200440. DOI: 10.1002/jcsm.12700. View

Wu X, Li Y, Zhang S, Zhou X . Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021; 11(7):3052-3059. PMC: 7847684. DOI: 10.7150/thno.54113. View

Miotto G, Rossetto M, Di Paolo M, Orian L, Venerando R, Roveri A . Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2019; 28:101328. PMC: 6812032. DOI: 10.1016/j.redox.2019.101328. View

10.

Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J . Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond). 2022; 42(2):88-116. PMC: 8822596. DOI: 10.1002/cac2.12250. View

11.

Liu H, Hu H, Li G, Zhang Y, Wu F, Liu X . Ferroptosis-Related Gene Signature Predicts Glioma Cell Death and Glioma Patient Progression. Front Cell Dev Biol. 2020; 8:538. PMC: 7363771. DOI: 10.3389/fcell.2020.00538. View

12.

Chen H, Xu C, Yu Q, Zhong C, Peng Y, Chen J . Comprehensive landscape of STEAP family functions and prognostic prediction value in glioblastoma. J Cell Physiol. 2020; 236(4):2988-3000. DOI: 10.1002/jcp.30060. View

13.

Liu F, Tang L, Li Q, Chen L, Pan Y, Yin Z . Single-cell transcriptomics uncover the key ferroptosis regulators contribute to cancer progression in head and neck squamous cell carcinoma. Front Mol Biosci. 2022; 9:962742. PMC: 9393303. DOI: 10.3389/fmolb.2022.962742. View

14.

Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M . KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2022; 51(D1):D587-D592. PMC: 9825424. DOI: 10.1093/nar/gkac963. View

15.

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C . Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. PMC: 6441206. DOI: 10.1186/s13045-019-0720-y. View

16.

Cheng J, Fan Y, Liu B, Zhou H, Wang J, Chen Q . ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep. 2019; 43(1):147-158. PMC: 6912066. DOI: 10.3892/or.2019.7419. View

17.

Li F, Long H, Zhou Z, Luo H, Xu S, Gao L . System X /GSH/GPX4 : An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. 2022; 13:910292. PMC: 9465090. DOI: 10.3389/fphar.2022.910292. View

18.

Yu Y, Jiang L, Wang H, Shen Z, Cheng Q, Zhang P . Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood. 2020; 136(6):726-739. PMC: 7414596. DOI: 10.1182/blood.2019002907. View

19.

LaPointe S, Perry A, Butowski N . Primary brain tumours in adults. Lancet. 2018; 392(10145):432-446. DOI: 10.1016/S0140-6736(18)30990-5. View

20.

Wu Z, Geng Y, Lu X, Shi Y, Wu G, Zhang M . Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019; 116(8):2996-3005. PMC: 6386716. DOI: 10.1073/pnas.1819728116. View