Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Depletion of SLC7A11 Sensitizes Nasopharyngeal Carcinoma Cells to Ionizing Radiation

Author(s): Fan Yang, Hongxun Gong, Shiyan Chen, Jianzhong Li, Ning Huang and Maoxin Wang*

Volume 31, Issue 4, 2024

Published on: 22 May, 2024

Page: [323 - 331] Pages: 9

DOI: 10.2174/0109298665308572240513113105

Price: $65

Abstract

Background: Radiotherapy is the primary treatment choice for Nasopharyngeal Carcinoma (NPC). However, its efficacy is compromised due to radioresistance. Ferroptosis, a novel iron-dependent regulated cell death induced by Ionizing Radiation (IR), plays a role in promoting cancer cell death. Yet, the relationship between enhanced ferroptosis and increased sensitivity of NPC cells to IR remains poorly understood.

Objective: This study aimed to explore the association between IR and ferroptosis in NPC, as well as the role of the ferroptosis repressor SLC7A11 in IR-treated NPC cells.

Methods: CNE1 and HNE-2 NPC cells were subjected to IR treatment. We performed qPCR and western blotting to evaluate the expression of ferroptosis-related genes in both control and IR-treated NPC cells. Additionally, we used the MTT assay to measure the viability of these NPC cells. JC-1 and DCFH-DA staining were employed to assess mitochondrial membrane potential and Reactive Oxygen Species (ROS) levels in both control and IR-treated NPC cells. Furthermore, we examined the levels of Fe2+, Malondialdehyde (MDA), reduced Glutathione (GSH), and oxidized glutathione (GSSG) in these cells. Moreover, we depleted SLC7A11 in IR-treated NPC cells to investigate its impact on the ferroptosis of these cells.

Results: IR upregulated the expression of ferroptosis-related genes, including SLC7A11, ACSL4, COX2, FTH1, and GPX4, in CNE1 and HNE-2 cells. IR treatment also resulted in decreased cell viability, disrupted mitochondrial membrane potential, increased ROS levels, altered glutathione levels, and elevated Fe2+ levels. Knockdown of SLC7A11 enhanced the sensitivity of NPC cells to IR.

Conclusion: IR may induce ferroptosis in NPC cells, and stimulating ferroptosis could potentially serve as a therapeutic strategy to enhance the efficacy of IR in treating NPC patients.

« Previous Next »
Graphical Abstract

[1]
Shah, A.B.; Nagalli, S. Nasopharyngeal Carcinoma In: StatPearls; StatPearls Publishing.: Treasure Island (FL), 2024.
[2]
Chen, Y.P.; Chan, A.T.C.; Le, Q.T.; Blanchard, P.; Sun, Y.; Ma, J. Nasopharyngeal carcinoma. Lancet, 2019, 394(10192), 64-80.
[http://dx.doi.org/10.1016/S0140-6736(19)30956-0] [PMID: 31178151]
[3]
Kam, M.K.M.; Leung, S.F.; Zee, B.; Chau, R.M.C.; Suen, J.J.S.; Mo, F.; Lai, M.; Ho, R.; Cheung, K.; Yu, B.K.H.; Chiu, S.K.W.; Choi, P.H.K.; Teo, P.M.L.; Kwan, W.; Chan, A.T.C. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J. Clin. Oncol., 2007, 25(31), 4873-4879.
[http://dx.doi.org/10.1200/JCO.2007.11.5501] [PMID: 17971582]
[4]
Peng, G.; Wang, T.; Yang, K.; Zhang, S.; Zhang, T.; Li, Q.; Han, J.; Wu, G. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother. Oncol., 2012, 104(3), 286-293.
[http://dx.doi.org/10.1016/j.radonc.2012.08.013] [PMID: 22995588]
[5]
Ai, Q.Y.H.; Hung, K.F.; So, T.Y.; Mo, F.K.F.; Tsung Anthony Chin, W.; Hui, E.P.; Ma, B.B.Y.; Ying, M.; King, A.D. Prognostic value of cervical nodal necrosis on staging imaging of nasopharyngeal carcinoma in era of intensity-modulated radiotherapy: A systematic review and meta-analysis. Cancer Imaging, 2022, 22(1), 24.
[http://dx.doi.org/10.1186/s40644-022-00462-6] [PMID: 35596198]
[6]
Mao, Y.P.; Tang, L.L.; Chen, L.; Sun, Y.; Qi, Z.Y.; Zhou, G.Q.; Liu, L.Z.; Li, L.; Lin, A.H.; Ma, J. Prognostic factors and failure patterns in non-metastatic nasopharyngeal carcinoma after intensity-modulated radiotherapy. Chin. J. Cancer, 2016, 35(1), 103.
[http://dx.doi.org/10.1186/s40880-016-0167-2] [PMID: 28031050]
[7]
Zhan, Y.; Fan, S. Multiple mechanisms involving in radioresistance of nasopharyngeal carcinoma. J. Cancer, 2020, 11(14), 4193-4204.
[http://dx.doi.org/10.7150/jca.39354] [PMID: 32368302]
[8]
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[9]
Li, J.; Cao, F.; Yin, H.; Huang, Z.; Lin, Z.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis., 2020, 11(2), 88.
[http://dx.doi.org/10.1038/s41419-020-2298-2] [PMID: 32015325]
[10]
Jiang, M.; Qiao, M.; Zhao, C.; Deng, J.; Li, X.; Zhou, C. Targeting ferroptosis for cancer therapy: Exploring novel strategies from its mechanisms and role in cancers. Transl. Lung Cancer Res., 2020, 9(4), 1569-1584.
[http://dx.doi.org/10.21037/tlcr-20-341] [PMID: 32953528]
[11]
Zhang, C.; Liu, X.; Jin, S.; Chen, Y.; Guo, R. Ferroptosis in cancer therapy: A novel approach to reversing drug resistance. Mol. Cancer, 2022, 21(1), 47.
[http://dx.doi.org/10.1186/s12943-022-01530-y] [PMID: 35151318]
[12]
Lei, G.; Zhang, Y.; Koppula, P.; Liu, X.; Zhang, J.; Lin, S.H.; Ajani, J.A.; Xiao, Q.; Liao, Z.; Wang, H.; Gan, B. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res., 2020, 30(2), 146-162.
[http://dx.doi.org/10.1038/s41422-019-0263-3] [PMID: 31949285]
[13]
Wang, L.; Chen, X.; Yan, C. Ferroptosis: An emerging therapeutic opportunity for cancer. Genes Dis., 2022, 9(2), 334-346.
[http://dx.doi.org/10.1016/j.gendis.2020.09.005] [PMID: 35224150]
[14]
Sia, J.; Szmyd, R.; Hau, E.; Gee, H.E. Molecular mechanisms of radiation-induced cancer cell death: A primer. Front. Cell Dev. Biol., 2020, 8, 41.
[http://dx.doi.org/10.3389/fcell.2020.00041] [PMID: 32117972]
[15]
Tian, Y.; Lu, J.; Hao, X.; Li, H.; Zhang, G.; Liu, X.; Li, X.; Zhao, C.; Kuang, W.; Chen, D.; Zhu, M. FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of parkinson’s disease. Neurotherapeutics, 2020, 17(4), 1796-1812.
[http://dx.doi.org/10.1007/s13311-020-00929-z] [PMID: 32959272]
[16]
Koppula, P.; Zhuang, L.; Gan, B. Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell, 2021, 12(8), 599-620.
[http://dx.doi.org/10.1007/s13238-020-00789-5] [PMID: 33000412]
[17]
Seibt, T.M.; Proneth, B.; Conrad, M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic. Biol. Med., 2019, 133, 144-152.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.09.014] [PMID: 30219704]
[18]
Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; Prokisch, H.; Trümbach, D.; Mao, G.; Qu, F.; Bayir, H.; Füllekrug, J.; Scheel, C.H.; Wurst, W.; Schick, J.A.; Kagan, V.E.; Angeli, J.P.F.; Conrad, M. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol., 2017, 13(1), 91-98.
[http://dx.doi.org/10.1038/nchembio.2239] [PMID: 27842070]
[19]
Lei, P.; Bai, T.; Sun, Y. Mechanisms of ferroptosis and relations with regulated cell death: A review. Front. Physiol., 2019, 10, 139.
[http://dx.doi.org/10.3389/fphys.2019.00139] [PMID: 30863316]
[20]
Xie, Y.; Kang, R.; Klionsky, D.J.; Tang, D. GPX4 in cell death, autophagy, and disease. Autophagy, 2023, 19(10), 2621-2638.
[http://dx.doi.org/10.1080/15548627.2023.2218764] [PMID: 37272058]
[21]
Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta Mol. Cell Res., 2016, 1863(12), 2977-2992.
[http://dx.doi.org/10.1016/j.bbamcr.2016.09.012] [PMID: 27646922]
[22]
Liu, X.; Chen, C.; Han, D.; Zhou, W.; Cui, Y.; Tang, X.; Xiao, C.; Wang, Y.; Gao, Y. SLC7A11/GPX4 inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity. Oxid. Med. Cell. Longev., 2022, 2022, 1-16.
[http://dx.doi.org/10.1155/2022/3192607] [PMID: 35757509]
[23]
Lin, W.; Wang, C.; Liu, G.; Bi, C.; Wang, X.; Zhou, Q.; Jin, H. SLC7A11/xCT in cancer: Biological functions and therapeutic implications. Am. J. Cancer Res., 2020, 10(10), 3106-3126.
[PMID: 33163260]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy