The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future
Abstract
:Simple Summary
Abstract
1. Introduction
Characteristics | Ferroptosis | Apoptosis | Necroptosis | Pyroptosis |
---|---|---|---|---|
Morphological features | small mitochondria, | unaltered mitochondria | swollen mitochondria | unaltered mitochondria |
vanishing mitochondrial cristae | apoptotic bodies | release of cytoplasmic constituents | Pore formation on plasma membrane | |
OMM rupture | cytoskeletal disintegration | plasma membrane rupture | Inflammasome formation | |
normal nucleus | chromatin condensation | chromatin condensation | Chromatin condensation | |
normal cell size | shrinkage of cell | swollen cell | swollen cell | |
Biochemical hallmarks | iron accumulation | PS exposure | No PS exposure * | secretion of IL-18 and IL-1β |
lipid peroxidation | DNA fragmentation | depletion of ATP | ||
Primary immune features | ICD | TCD | ICD | ICD |
Signaling pathways | TFRC IREB/SLC11A2 | TNFRSF1A/FADD TRAILR1/2 Caspases-9/-3/-7 P53/PUMA BCL-2/BAX/BAK cytochrome c/APAF-1 endoplasmic reticulum | TNFR1/RIPK1 RIPK1/RIPK3/MLKL PKC-MAPK-AP-1 | release of mtDNA in cytosol NLRP3/AIM2 caspase-1/ IL-18/IL-1β capase-1/4/5/11/GSDMD caspase-3/ GSDME |
Haem/HO-1 FTH1/FTL/Prominin 2 NCOA4/ferrotinophagy CISD1/2/Fe-S ACSLs/LPCAT3/ALOXs | ||||
GSH/GPX4, MVA/HMGCR | ||||
FSP1/CoQ10 DHODH/CoQ10 |
Target | Approaches | Phase of Clinical Development | Reference |
---|---|---|---|
Iron activators | |||
↑Transferrin | lapatinib | in vitro model | 28827805 [37] |
↑Transferrin | lapatinib | in vitro model | 27441659 [38] |
↓SLC40A1 | lapatinib | Marketed | NCT00667251 [38] |
↑Iron | UV light | Preclinical animal model | 32804509 [39] |
↑Iron | MOF-Fe2+ | Preclinical animal model | 32944722 [40] |
↑Iron | Fe3O4 nanocapcules | in vitro model | 34225869 [41] |
↑Iron | neratinib | Preclinical animal model | 31409375 [42] |
↑Iron | neratinib | Marketed | NCT04366713 |
↑Iron | neratinib | Marketed | NCT03377387 |
↑Iron | Fe3+-PDA NP | in vitro model | 33808898 [43] |
↓CISD1/2, ↑Iron | MAD-28 | Preclinical animal model | 25762074 [44] |
↑HO-1 | MI-463 | in vitro model | 32945449 [45] |
↑HO-1 | SGNI | Preclinical animal model | 33827043 [46] |
Ferritinophagy activators | |||
↑Iron | artesunate | Phase I trials | NCT00764036 [47] |
Lipid peroxides activators | |||
↑ACSL1 | α-eleostearic acid | Preclinical animal model | 33854057 [48] |
↑ACSL4 | Polyphyllin III | Preclinical animal model | 34040532 [49] |
System xc- inhibitors | |||
↓SLC7A11 | Erastin | in vitro model | 33672555 [50] |
↓SLC7A11 | Lidocaine | in vitro model | 34122108 [51] |
↓SLC7A11 | miR-106a-5p | in vitro model | 33686957 [52] |
↓SLC7A11 | sulfasalazine | Phase I trials | NCT03847311 |
↓SLC7A11 | metformin, sulfasalazine | in vitro model | 34162423 [53] |
↓SLC7A11 | 18-β-glycyrrhetinic acid | in vitro model | 34271106 [54] |
GPX4 pathway inhibitors | |||
↓GPX4 | JQ1+BTZ | Preclinical animal model | 32937365 [55] |
↓NRF2 | overexpression of GSK-3β | Preclinical animal model | 32642794 [56] |
↓GPX4 | RSL-3 | Preclinical animal model | 34170581 [57] |
↓GPX4 | metformin | Preclinical animal model | 33522578 [58] |
↓GPX4 | DMOCPTL | Preclinical animal model | 33472669 [59] |
↓GPX4, MDM2 | Compound 3d | Preclinical animal model | 33725632 [60] |
↓TYRO3 | LDC1267 | Preclinical animal model | 33855973 [32] |
↓DHODH | leflunomide | Preclinical animal model | 32034120 [61] |
↓DHODH | BQR, leflunomide, 4SC-101 | in vitro model | 28196676 [62] |
HMGCR inhibitor | |||
↓HMGCR | fluvastatin | Phase I trials | 19728082 [63] |
↓HMCGR | atorvastatin | Phase II trials | NCT00816244 [64] |
2. Inducing Ferroptosis by Iron Toxicity and Lipid Peroxides
3. Inducing Ferroptosis by Inhibiting Antioxidant Defense
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Liu, J.; Shen, J.X.; Wen, X.F.; Guo, Y.X.; Zhang, G.J. Targeting Notch degradation system provides promise for breast cancer therapeutics. Crit. Rev. Oncol. Hematol. 2016, 104, 21–29. [Google Scholar] [CrossRef] [Green Version]
- Ono, M.; Ogilvie, J.M.; Wilson, J.S.; Green, H.J.; Chambers, S.K.; Ownsworth, T.; Shum, D.H. A meta-analysis of cognitive impairment and decline associated with adjuvant chemotherapy in women with breast cancer. Front. Oncol. 2015, 5, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El Ansari, R.; McIntyre, A.; Craze, M.L.; Ellis, I.O.; Rakha, E.A.; Green, A.R. Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations. Histopathology 2018, 72, 183–190. [Google Scholar] [CrossRef] [PubMed]
- Fang, Y.; Tian, S.; Pan, Y.; Li, W.; Wang, Q.; Tang, Y.; Yu, T.; Wu, X.; Shi, Y.; Ma, P.; et al. Pyroptosis: A new frontier in cancer. Biomed. Pharmacother 2020, 121, 109595. [Google Scholar] [CrossRef]
- Li, J.; Cao, F.; Yin, H.L.; Huang, Z.J.; Lin, Z.T.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis. 2020, 11, 88. [Google Scholar] [CrossRef]
- Gudipaty, S.A.; Conner, C.M.; Rosenblatt, J.; Montell, D.J. Unconventional Ways to Live and Die: Cell Death and Survival in Development, Homeostasis, and Disease. Annu. Rev. Cell Dev. Biol. 2018, 34, 311–332. [Google Scholar] [CrossRef]
- Khan, I.; Yousif, A.; Chesnokov, M.; Hong, L.; Chefetz, I. A decade of cell death studies: Breathing new life into necroptosis. Pharmacol Ther. 2021, 220, 107717. [Google Scholar] [CrossRef] [PubMed]
- Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 2020, 17, 395–417. [Google Scholar] [CrossRef] [PubMed]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fulda, S.; Debatin, K.M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006, 25, 4798–4811. [Google Scholar] [CrossRef] [Green Version]
- Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001, 15, 2922–2933. [Google Scholar]
- Puthalakath, H.; Strasser, A. Keeping killers on a tight leash: Transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 2002, 9, 505–512. [Google Scholar] [CrossRef]
- Hetz, C.; Zhang, K.; Kaufman, R.J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 2020, 21, 421–438. [Google Scholar] [CrossRef] [PubMed]
- Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 2019, 29, 347–364. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Du, T.; Gao, J.; Li, P.; Wang, Y.; Qi, Q.; Liu, X.; Li, J.; Wang, C.; Du, L. Pyroptosis, metabolism, and tumor immune microenvironment. Clin. Transl. Med. 2021, 11, e492. [Google Scholar] [CrossRef] [PubMed]
- Kayagaki, N.; Stowe, I.B.; Lee, B.L.; O’Rourke, K.; Anderson, K.; Warming, S.; Cuellar, T.; Haley, B.; Roose-Girma, M.; Phung, Q.T.; et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015, 526, 666–671. [Google Scholar] [CrossRef]
- Man, S.M.; Kanneganti, T.D. Gasdermin D: The long-awaited executioner of pyroptosis. Cell Res. 2015, 25, 1183–1184. [Google Scholar] [CrossRef] [Green Version]
- Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015, 526, 660–665. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Gao, W.; Shi, X.; Ding, J.; Liu, W.; He, H.; Wang, K.; Shao, F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 2017, 547, 99–103. [Google Scholar] [CrossRef]
- Zhang, Z.; Zhang, Y.; Xia, S.; Kong, Q.; Li, S.; Liu, X.; Junqueira, C.; Meza-Sosa, K.F.; Mok, T.M.Y.; Ansara, J.; et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 2020, 579, 415–420. [Google Scholar] [CrossRef]
- Tang, R.; Xu, J.; Zhang, B.; Liu, J.; Liang, C.; Hua, J.; Meng, Q.; Yu, X.; Shi, S. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J. Hematol. Oncol. 2020, 13, 110. [Google Scholar] [CrossRef] [PubMed]
- Efferth, T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin. Cancer Biol. 2017, 46, 65–83. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.X.; Liu, Z.N.; Ye, J.; Sha, M.; Qian, H.; Bu, X.H.; Luan, Z.Y.; Xu, X.L.; Huang, A.H.; Yuan, D.L.; et al. Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression. Cell Biol. Int. 2014, 38, 639–646. [Google Scholar] [CrossRef] [PubMed]
- Cui, C.; Feng, H.; Shi, X.; Wang, Y.; Feng, Z.; Liu, J.; Han, Z.; Fu, J.; Fu, Z.; Tong, H. Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor beta1 and interleukin-10. Int. Immunopharmacol. 2015, 27, 110–121. [Google Scholar] [CrossRef]
- Qian, P.; Zhang, Y.W.; Zhou, Z.H.; Liu, J.Q.; Yue, S.Y.; Guo, X.L.; Sun, L.Q.; Lv, X.T.; Chen, J.Q. Artesunate enhances gammadelta T-cell-mediated antitumor activity through augmenting gammadelta T-cell function and reversing immune escape of HepG2 cells. Immunopharmacol. Immunotoxicol. 2018, 40, 107–116. [Google Scholar] [CrossRef] [PubMed]
- Duong, B.H.; Onizawa, M.; Oses-Prieto, J.A.; Advincula, R.; Burlingame, A.; Malynn, B.A.; Ma, A. A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity. Immunity 2015, 42, 55–67. [Google Scholar] [CrossRef] [Green Version]
- Guo, J.; Xu, B.; Han, Q.; Zhou, H.; Xia, Y.; Gong, C.; Dai, X.; Li, Z.; Wu, G. Ferroptosis: A Novel Anti-tumor Action for Cisplatin. Cancer Res. Treat. 2018, 50, 445–460. [Google Scholar] [CrossRef] [Green Version]
- Zhang, C.C.; Li, C.G.; Wang, Y.F.; Xu, L.H.; He, X.H.; Zeng, Q.Z.; Zeng, C.Y.; Mai, F.Y.; Hu, B.; Ouyang, D.Y. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis 2019, 24, 312–325. [Google Scholar] [CrossRef]
- 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.; et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012, 149, 1060–1072. [Google Scholar] [CrossRef] [Green Version]
- Chen, X.; Kang, R.; Kroemer, G.; Tang, D. Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 2021, 18, 280–296. [Google Scholar] [CrossRef]
- Jiang, Z.; Lim, S.O.; Yan, M.; Hsu, J.L.; Yao, J.; Wei, Y.; Chang, S.S.; Yamaguchi, H.; Lee, H.H.; Ke, B.; et al. TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J. Clin. Investig. 2021, 131, e139434. [Google Scholar] [CrossRef] [PubMed]
- Tsoi, J.; Robert, L.; Paraiso, K.; Galvan, C.; Sheu, K.M.; Lay, J.; Wong, D.J.L.; Atefi, M.; Shirazi, R.; Wang, X.; et al. Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress. Cancer Cell 2018, 33, 890–904. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Viswanathan, V.S.; Ryan, M.J.; Dhruv, H.D.; Gill, S.; Eichhoff, O.M.; Seashore-Ludlow, B.; Kaffenberger, S.D.; Eaton, J.K.; Shimada, K.; Aguirre, A.J.; et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017, 547, 453–457. [Google Scholar] [CrossRef] [PubMed]
- Friedmann Angeli, J.P.; Krysko, D.V.; Conrad, M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat. Rev. Cancer 2019, 19, 405–414. [Google Scholar] [CrossRef] [PubMed]
- Wang, K.J.; Meng, X.Y.; Chen, J.F.; Wang, K.Y.; Zhou, C.; Yu, R.; Ma, Q. Emodin Induced Necroptosis and Inhibited Glycolysis in the Renal Cancer Cells by Enhancing ROS. Oxid. Med. Cell Longev. 2021, 2021, 8840590. [Google Scholar]
- Ma, S.; Dielschneider, R.F.; Henson, E.S.; Xiao, W.; Choquette, T.R.; Blankstein, A.R.; Chen, Y.; Gibson, S.B. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS ONE 2017, 12, e0182921. [Google Scholar] [CrossRef] [Green Version]
- Ma, S.; Henson, E.S.; Chen, Y.; Gibson, S.B. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016, 7, e2307. [Google Scholar] [CrossRef] [Green Version]
- Zhu, J.; Dai, P.; Liu, F.; Li, Y.; Qin, Y.; Yang, Q.; Tian, R.; Fan, A.; Medeiros, S.F.; Wang, Z.; et al. Upconverting Nanocarriers Enable Triggered Microtubule Inhibition and Concurrent Ferroptosis Induction for Selective Treatment of Triple-Negative Breast Cancer. Nano Lett. 2020, 20, 6235–6245. [Google Scholar] [CrossRef]
- Xu, X.; Chen, Y.; Zhang, Y.; Yao, Y.; Ji, P. Highly stable and biocompatible hyaluronic acid-rehabilitated nanoscale MOF-Fe(2+) induced ferroptosis in breast cancer cells. J. Mater. Chem B 2020, 8, 9129–9138. [Google Scholar] [CrossRef]
- Antoniak, M.A.; Pazik, R.; Bazylinska, U.; Wiwatowski, K.; Tomaszewska, A.; Kulpa-Greszta, M.; Adamczyk-Grochala, J.; Wnuk, M.; Mackowski, S.; Lewinska, A.; et al. Multimodal polymer encapsulated CdSe/Fe3O4 nanoplatform with improved biocompatibility for two-photon and temperature stimulated bioapplications. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 127, 112224. [Google Scholar] [CrossRef]
- Nagpal, A.; Redvers, R.P.; Ling, X.; Ayton, S.; Fuentes, M.; Tavancheh, E.; Diala, I.; Lalani, A.; Loi, S.; David, S.; et al. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2(+ve) breast cancer metastasis. Breast Cancer Res. 2019, 21, 94. [Google Scholar] [CrossRef]
- Nieto, C.; Vega, M.A.; Martin Del Valle, E.M. Tailored-Made Polydopamine Nanoparticles to Induce Ferroptosis in Breast Cancer Cells in Combination with Chemotherapy. Int. J. Mol. Sci. 2021, 22, 3161. [Google Scholar] [CrossRef]
- Bai, F.; Morcos, F.; Sohn, Y.S.; Darash-Yahana, M.; Rezende, C.O.; Lipper, C.H.; Paddock, M.L.; Song, L.; Luo, Y.; Holt, S.H.; et al. The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer. Proc. Natl. Acad. Sci. USA 2015, 112, 3698–3703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kato, I.; Kasukabe, T.; Kumakura, S. MeninMLL inhibitors induce ferroptosis and enhance the antiproliferative activity of auranofin in several types of cancer cells. Int. J. Oncol. 2020, 57, 1057–1071. [Google Scholar] [PubMed]
- Du, J.; Wang, L.; Huang, X.; Zhang, N.; Long, Z.; Yang, Y.; Zhong, F.; Zheng, B.; Lan, W.; Lin, W.; et al. Shuganning injection, a traditional Chinese patent medicine, induces ferroptosis and suppresses tumor growth in triple-negative breast cancer cells. Phytomedicine 2021, 85, 153551. [Google Scholar] [CrossRef] [PubMed]
- von Hagens, C.; Walter-Sack, I.; Goeckenjan, M.; Osburg, J.; Storch-Hagenlocher, B.; Sertel, S.; Elsasser, M.; Remppis, B.A.; Edler, L.; Munzinger, J.; et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res. Treat. 2017, 164, 359–369. [Google Scholar] [CrossRef]
- Beatty, A.; Singh, T.; Tyurina, Y.Y.; Tyurin, V.A.; Samovich, S.; Nicolas, E.; Maslar, K.; Zhou, Y.; Cai, K.Q.; Tan, Y.; et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 2021, 12, 2244. [Google Scholar] [CrossRef]
- Zhou, Y.; Yang, J.; Chen, C.; Li, Z.; Chen, Y.; Zhang, X.; Wang, L.; Zhou, J. Polyphyllin -Induced Ferroptosis in MDA-MB-231 Triple-Negative Breast Cancer Cells can Be Protected Against by KLF4-Mediated Upregulation of xCT. Front. Pharmacol. 2021, 12, 670224. [Google Scholar] [CrossRef] [PubMed]
- Lee, N.; Carlisle, A.E.; Peppers, A.; Park, S.J.; Doshi, M.B.; Spears, M.E.; Kim, D. xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers. Antioxidants 2021, 10, 317. [Google Scholar] [CrossRef] [PubMed]
- Sun, D.; Li, Y.C.; Zhang, X.Y. Lidocaine Promoted Ferroptosis by Targeting miR-382-5p /SLC7A11 Axis in Ovarian and Breast Cancer. Front. Pharmacol. 2021, 12, 681223. [Google Scholar] [CrossRef]
- Zhang, H.; Ge, Z.; Wang, Z.; Gao, Y.; Wang, Y.; Qu, X. Circular RNA RHOT1 promotes progression and inhibits ferroptosis via mir-106a-5p/STAT3 axis in breast cancer. Aging (Albany NY) 2021, 13, 8115–8126. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.; Zhou, Y.; Xie, S.; Wang, J.; Li, Z.; Chen, L.; Mao, M.; Chen, C.; Huang, A.; Chen, Y.; et al. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J. Exp. Clin. Cancer Res. 2021, 40, 206. [Google Scholar] [CrossRef] [PubMed]
- Wen, Y.; Chen, H.; Zhang, L.; Wu, M.; Zhang, F.; Yang, D.; Shen, J.; Chen, J. Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radic. Biol. Med. 2021, 173, 41–51. [Google Scholar] [CrossRef] [PubMed]
- Verma, N.; Vinik, Y.; Saroha, A.; Nair, N.U.; Ruppin, E.; Mills, G.; Karn, T.; Dubey, V.; Khera, L.; Raj, H.; et al. Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis. Sci. Adv. 2020, 6, eaba8968. [Google Scholar] [CrossRef]
- Wu, X.; Liu, C.; Li, Z.; Gai, C.; Ding, D.; Chen, W.; Hao, F.; Li, W. Regulation of GSK3beta/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Mol. Cell Biochem. 2020, 473, 217–228. [Google Scholar] [CrossRef]
- Song, R.; Li, T.; Ye, J.; Sun, F.; Hou, B.; Saeed, M.; Gao, J.; Wang, Y.; Zhu, Q.; Xu, Z.; et al. Acidity-Activatable Dynamic Nanoparticles Boosting Ferroptotic Cell Death for Immunotherapy of Cancer. Adv. Mater. 2021, 33, e2101155. [Google Scholar] [CrossRef] [PubMed]
- Hou, Y.; Cai, S.; Yu, S.; Lin, H. Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer. Acta Biochim. Biophys. Sin. (Shanghai) 2021, 53, 333–341. [Google Scholar] [CrossRef]
- Ding, Y.; Chen, X.; Liu, C.; Ge, W.; Wang, Q.; Hao, X.; Wang, M.; Chen, Y.; Zhang, Q. Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells. J. Hematol. Oncol. 2021, 14, 19. [Google Scholar] [CrossRef]
- Liu, S.J.; Zhao, Q.; Peng, C.; Mao, Q.; Wu, F.; Zhang, F.H.; Feng, Q.S.; He, G.; Han, B. Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation. Eur. J. Med. Chem. 2021, 217, 113359. [Google Scholar] [CrossRef]
- Hubackova, S.; Davidova, E.; Boukalova, S.; Kovarova, J.; Bajzikova, M.; Coelho, A.; Terp, M.G.; Ditzel, H.J.; Rohlena, J.; Neuzil, J. Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors. Cell Death Dis. 2020, 11, 110. [Google Scholar] [CrossRef]
- Mohamad Fairus, A.K.; Choudhary, B.; Hosahalli, S.; Kavitha, N.; Shatrah, O. Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells. Biochimie 2017, 135, 154–163. [Google Scholar] [CrossRef] [PubMed]
- Garwood, E.R.; Kumar, A.S.; Baehner, F.L.; Moore, D.H.; Au, A.; Hylton, N.; Flowers, C.I.; Garber, J.; Lesnikoski, B.A.; Hwang, E.S.; et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res. Treat. 2010, 119, 137–144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bjarnadottir, O.; Romero, Q.; Bendahl, P.O.; Jirstrom, K.; Ryden, L.; Loman, N.; Uhlen, M.; Johannesson, H.; Rose, C.; Grabau, D.; et al. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res. Treat. 2013, 138, 499–508. [Google Scholar] [CrossRef] [PubMed]
- Yang, W.S.; Stockwell, B.R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 2008, 15, 234–245. [Google Scholar] [CrossRef] [Green Version]
- Geng, N.; Shi, B.J.; Li, S.L.; Zhong, Z.Y.; Li, Y.C.; Xua, W.L.; Zhou, H.; Cai, J.H. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3826–3836. [Google Scholar]
- Gao, M.; Monian, P.; Quadri, N.; Ramasamy, R.; Jiang, X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol. Cell 2015, 59, 298–308. [Google Scholar] [CrossRef] [Green Version]
- Kwon, M.Y.; Park, E.; Lee, S.J.; Chung, S.W. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget 2015, 6, 24393–24403. [Google Scholar] [CrossRef] [Green Version]
- Fisher, J.; Devraj, K.; Ingram, J.; Slagle-Webb, B.; Madhankumar, A.B.; Liu, X.; Klinger, M.; Simpson, I.A.; Connor, J.R. Ferritin: A novel mechanism for delivery of iron to the brain and other organs. Am. J. Physiol. Cell Physiol. 2007, 293, C641–C649. [Google Scholar] [CrossRef] [Green Version]
- Brown, C.W.; Amante, J.J.; Chhoy, P.; Elaimy, A.L.; Liu, H.; Zhu, L.J.; Baer, C.E.; Dixon, S.J.; Mercurio, A.M. Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export. Dev. Cell 2019, 51, 575–586.e4. [Google Scholar] [CrossRef]
- Gammella, E.; Recalcati, S.; Rybinska, I.; Buratti, P.; Cairo, G. Iron-induced damage in cardiomyopathy: Oxidative-dependent and independent mechanisms. Oxid. Med. Cell Longev. 2015, 2015, 230182. [Google Scholar] [CrossRef] [Green Version]
- Gao, M.; Monian, P.; Pan, Q.; Zhang, W.; Xiang, J.; Jiang, X. Ferroptosis is an autophagic cell death process. Cell Res. 2016, 26, 1021–1032. [Google Scholar] [CrossRef] [Green Version]
- Hou, W.; Xie, Y.; Song, X.; Sun, X.; Lotze, M.T.; Zeh, H.J., 3rd; Kang, R.; Tang, D. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016, 12, 1425–1428. [Google Scholar] [CrossRef]
- Alvarez, S.W.; Sviderskiy, V.O.; Terzi, E.M.; Papagiannakopoulos, T.; Moreira, A.L.; Adams, S.; Sabatini, D.M.; Birsoy, K.; Possemato, R. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 2017, 551, 639–643. [Google Scholar] [CrossRef] [PubMed]
- Du, J.; Wang, T.; Li, Y.; Zhou, Y.; Wang, X.; Yu, X.; Ren, X.; An, Y.; Wu, Y.; Sun, W.; et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic. Biol. Med. 2019, 131, 356–369. [Google Scholar] [CrossRef] [PubMed]
- Kim, E.H.; Shin, D.; Lee, J.; Jung, A.R.; Roh, J.L. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett. 2018, 432, 180–190. [Google Scholar] [CrossRef] [PubMed]
- 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, 838–844. [Google Scholar] [CrossRef]
- Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascon, S.; Hatzios, S.K.; Kagan, V.E.; et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017, 171, 273–285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, W.S.; Kim, K.J.; Gaschler, M.M.; Patel, M.; Shchepinov, M.S.; Stockwell, B.R. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA 2016, 113, E4966–E4975. [Google Scholar] [CrossRef] [Green Version]
- Yang, W.S.; Stockwell, B.R. Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol. 2016, 26, 165–176. [Google Scholar] [CrossRef] [Green Version]
- Dixon, S.J.; Winter, G.E.; Musavi, L.S.; Lee, E.D.; Snijder, B.; Rebsamen, M.; Superti-Furga, G.; Stockwell, B.R. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem. Biol. 2015, 10, 1604–1609. [Google Scholar] [CrossRef] [PubMed]
- Doll, S.; Proneth, B.; Tyurina, Y.Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A.; et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 2017, 13, 91–98. [Google Scholar] [CrossRef] [PubMed]
- Kagan, V.E.; Mao, G.; Qu, F.; Angeli, J.P.; Doll, S.; Croix, C.S.; Dar, H.H.; Liu, B.; Tyurin, V.A.; Ritov, V.B.; et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 2017, 13, 81–90. [Google Scholar] [CrossRef] [PubMed]
- Yuan, H.; Li, X.; Zhang, X.; Kang, R.; Tang, D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem. Biophys. Res. Commun. 2016, 478, 1338–1343. [Google Scholar] [CrossRef] [PubMed]
- Eling, N.; Reuter, L.; Hazin, J.; Hamacher-Brady, A.; Brady, N.R. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015, 2, 517–532. [Google Scholar] [CrossRef] [Green Version]
- Lin, R.; Zhang, Z.; Chen, L.; Zhou, Y.; Zou, P.; Feng, C.; Wang, L.; Liang, G. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. Cancer Lett. 2016, 381, 165–175. [Google Scholar] [CrossRef]
- Ooko, E.; Saeed, M.E.; Kadioglu, O.; Sarvi, S.; Colak, M.; Elmasaoudi, K.; Janah, R.; Greten, H.J.; Efferth, T. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 2015, 22, 1045–1054. [Google Scholar] [CrossRef]
- Klayman, D.L. Qinghaosu (artemisinin): An antimalarial drug from China. Science 1985, 228, 1049–1055. [Google Scholar] [CrossRef] [Green Version]
- Mao, C.; Liu, X.; Zhang, Y.; Lei, G.; Yan, Y.; Lee, H.; Koppula, P.; Wu, S.; Zhuang, L.; Fang, B.; et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 2021, 593, 586–590. [Google Scholar] [CrossRef]
- Wang, F.; Min, J. DHODH tangoing with GPX4 on the ferroptotic stage. Signal. Transduct. Target. Ther. 2021, 6, 244. [Google Scholar] [CrossRef] [PubMed]
- Warner, G.J.; Berry, M.J.; Moustafa, M.E.; Carlson, B.A.; Hatfield, D.L.; Faust, J.R. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine. J. Biol. Chem. 2000, 275, 28110–28119. [Google Scholar] [CrossRef] [Green Version]
- Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019, 575, 688–692. [Google Scholar] [CrossRef] [PubMed]
- Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019, 575, 693–698. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Bermudez, J.; Birsoy, K. A mitochondrial gatekeeper that helps cells escape death by ferroptosis. Nature 2021, 593, 514–515. [Google Scholar] [CrossRef]
- Qiao, J.; Chen, Y.; Mi, Y.; Jin, H.; Huang, T.; Liu, L.; Gong, L.; Wang, L.; Wang, Q.; Zou, Z. NR5A2 synergizes with NCOA3 to induce breast cancer resistance to BET inhibitor by upregulating NRF2 to attenuate ferroptosis. Biochem. Biophys. Res. Commun. 2020, 530, 402–409. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Lin, H.-Y.; Ho, H.-W.; Chang, Y.-H.; Wei, C.-J.; Chu, P.-Y. The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future. Cancers 2021, 13, 4576. https://doi.org/10.3390/cancers13184576
Lin H-Y, Ho H-W, Chang Y-H, Wei C-J, Chu P-Y. The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future. Cancers. 2021; 13(18):4576. https://doi.org/10.3390/cancers13184576
Chicago/Turabian StyleLin, Hung-Yu, Hui-Wen Ho, Yen-Hsiang Chang, Chun-Jui Wei, and Pei-Yi Chu. 2021. "The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future" Cancers 13, no. 18: 4576. https://doi.org/10.3390/cancers13184576