Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin
Tóm tắt
Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells.
Tài liệu tham khảo
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85. https://doi.org/10.1016/j.cell.2017.09.021.
Kuang F, Liu J, Tang D, Kang R. Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol. 2020;8:586578. https://doi.org/10.3389/fcell.2020.586578.
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22(4):266–82. https://doi.org/10.1038/s41580-020-00324-8.
Feng H, Stockwell BR. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16(5):e2006203. https://doi.org/10.1371/journal.pbio.2006203.
Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022. https://doi.org/10.1038/s41568-022-00459-0.
Zhang DL, Ghosh MC, Rouault TA. The physiological functions of iron regulatory proteins in iron homeostasis—an update. Front Pharmacol. 2014;5:124. https://doi.org/10.3389/fphar.2014.00124.
Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F. Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells. J Biol Chem. 2000;275(29):22220–8. https://doi.org/10.1074/jbc.M001478200.
Turcu AL, Versini A, Khene N, Gaillet C, Cañeque T, Müller S, et al. DMT1 inhibitors kill cancer stem cells by blocking lysosomal iron translocation. Chemistry (Weinheim an der Bergstrasse, Germany). 2020;26(33):7369–73. https://doi.org/10.1002/chem.202000159.
Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem. 2017;9(10):1025–33. https://doi.org/10.1038/nchem.2778.
Versini A, Colombeau L, Hienzsch A, Gaillet C, Retailleau P, Debieu S, et al. Salinomycin derivatives kill breast cancer stem cells by lysosomal iron targeting. Chemistry (Weinheim an der Bergstrasse, Germany). 2020;26(33):7416–24. https://doi.org/10.1002/chem.202000335.
Kim SY, Chu KC, Lee HR, Lee KS, Carey TE. Establishment and characterization of nine new head and neck cancer cell lines. Acta Otolaryngol. 1997;117(5):775–84. https://doi.org/10.3109/00016489709113477.
Yanatori I, Kishi F. DMT1 and iron transport. Free Radical Biol Med. 2019;133:55–63. https://doi.org/10.1016/j.freeradbiomed.2018.07.020.
Yan R, Xie E, Li Y, Li J, Zhang Y, Chi X, et al. The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis. Cell Res. 2022. https://doi.org/10.1038/s41422-022-00642-w.
Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA, et al. Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther. 2021;6(1):49. https://doi.org/10.1038/s41392-020-00428-9.
Drummen GP, van Liebergen LC, Op den Kamp JA, Post JA. C11-BODIPY(581/591), an oxidation-sensitive fluorescent lipid peroxidation probe: (micro)spectroscopic characterization and validation of methodology. Free Radical Biol Med. 2002;33(4):473–90. https://doi.org/10.1016/s0891-5849(02)00848-1.
Leidgens S, Bullough KZ, Shi H, Li F, Shakoury-Elizeh M, Yabe T, et al. Each member of the poly-r(C)-binding protein 1 (PCBP) family exhibits iron chaperone activity toward ferritin. J Biol Chem. 2013;288(24):17791–802. https://doi.org/10.1074/jbc.M113.460253.
Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388(6641):482–8. https://doi.org/10.1038/41343.
Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA. 2002;99(19):12345–50. https://doi.org/10.1073/pnas.192423399.
Philpott CC, Ryu MS, Frey A, Patel S. Cytosolic iron chaperones: proteins delivering iron cofactors in the cytosol of mammalian cells. J Biol Chem. 2017;292(31):12764–71. https://doi.org/10.1074/jbc.R117.791962.
Lv H, Shang P. The significance, trafficking and determination of labile iron in cytosol, mitochondria and lysosomes. Metallomics. 2018;10(7):899–916. https://doi.org/10.1039/c8mt00048d.
Tsuji M, Ueda S, Hirayama T, Okuda K, Sakaguchi Y, Isono A, et al. FRET-based imaging of transbilayer movement of pepducin in living cells by novel intracellular bioreductively activatable fluorescent probes. Org Biomol Chem. 2013;11(18):3030–7. https://doi.org/10.1039/c3ob27445d.
Chen X, Yu C, Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:590226. https://doi.org/10.3389/fcell.2020.590226.
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12(8):1425–8. https://doi.org/10.1080/15548627.2016.1187366.
Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell. 2019;51(5):575-86.e4. https://doi.org/10.1016/j.devcel.2019.10.007.
Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551(7682):639–43. https://doi.org/10.1038/nature24637.
Yuan H, Li X, Zhang X, Kang R, Tang D. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun. 2016;478(2):838–44. https://doi.org/10.1016/j.bbrc.2016.08.034.
Kim EH, Shin D, Lee J, Jung AR, Roh JL. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett. 2018;432:180–90. https://doi.org/10.1016/j.canlet.2018.06.018.
Li Y, Wang X, Huang Z, Zhou Y, Xia J, Hu W, et al. CISD3 inhibition drives cystine-deprivation induced ferroptosis. Cell Death Dis. 2021;12(9):839. https://doi.org/10.1038/s41419-021-04128-2.
Lee J, You JH, Shin D, Roh JL. Inhibition of glutaredoxin 5 predisposes cisplatin-resistant head and neck cancer cells to ferroptosis. Theranostics. 2020;10(17):7775–86. https://doi.org/10.7150/thno.46903.
Lee J, You JH, Roh JL. Poly(rC)-binding protein 1 represses ferritinophagy-mediated ferroptosis in head and neck cancer. Redox Biol. 2022;51:102276. https://doi.org/10.1016/j.redox.2022.102276.