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Pacidusin B isolated from Phyllanthus acidus triggers ferroptotic cell death in HT1080 cells |
| Guangyu Zhu1,2, Dian Luo1,2, Yueqin Zhao1,2, Zhengrui Xiang1,2, Chao Chen1,3, Na Li1, Xiaojiang Hao1,4, Xiao Ding1,4, Yingjun Zhang1,5, Yuhan Zhao1 |
1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China;
2. University of Chinese Academy of Sciences, Beijing, 100049, China;
3. Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China;
4. Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China;
5. Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China |
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Abstract Cancer cells generally exhibit ‘iron addiction’ phenotypes, which contribute to their vulnerability to ferroptosis inducers. Ferroptosis is a newly discovered form of programmed cell death caused by iron-dependent lipid peroxidation. In the present study, pacidusin B, a dichapetalin-type triterpenoid from Phyllanthus acidus (L.) Skeels (Euphorbiaceae), induces ferroptosis in the HT1080 human fibrosarcoma cell line. Cells treated with pacidusin B exhibited the morphological characteristic ‘ballooning’ phenotype of ferroptosis. The biochemical hallmarks of ferroptosis were also observed in pacidusin B-treated cells. Both oxidative stress and ER stress play significant roles in pacidusin B-induced ferroptosis. The activation of the PERK-Nrf2-HO-1 signaling pathway led to iron overload, while inhibition of GPX4 further sensitized cancer cells to ferroptosis. Furthermore, the molecular docking study showed that pacidusin B docked in the same pocket in xCT as the ferroptosis inducer erastin. These results revealed that pacidusin B exerts anticancer effects via inducing ER-mediated ferroptotic cell death.
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| Keywords
Ferroptosis
Pacidusin B
ER stress
PERK-Nrf2-HO-1 pathway
xCT
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| Fund:This research was supported financially by grants from the CAS “Light of West China” Program, National Natural Science Foundation of China (82073740, 82293683 (82293680), 32270426, and 32000548), CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-5-004), Natural Science Foundation of Yunnan Province (202301AT070282), Yunnan Revitalization Talent Support Program “Young Talent” Project (YNQR-QNRC-2019-091), the CAS Pioneer Hundred Talents Program, talent program from Kunming Institute of Botany CAS, and grant from Yunnan Province Science and Technology Department (202305AH340005). |
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Corresponding Authors:
Xiao Ding,E-mail:dingxiao@mail.kib.ac.cn;Yingjun Zhang,E-mail:zhangyj@mail.kib.ac.cn;Yuhan Zhao,E-mail:zhaoyuhan@mail.kib.ac.cn
E-mail: dingxiao@mail.kib.ac.cn;zhangyj@mail.kib.ac.cn;zhaoyuhan@mail.kib.ac.cn
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Issue Date: 14 October 2024
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[1] Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3(3):285-96.
[2] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-72.
[3] Dodson M, Castro-Portuguez R, Zhang DD. Nrf2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23: 101107.
[4] Herbette S, Roeckel-Drevet P, Drevet JR. Seleno-independent glutathione peroxidases. More than simple antioxidant scavengers. FEBS J. 2007;274(9):2163-80.
[5] Toppo S, Vanin S, Bosello V, Tosatto SC. Evolutionary and structural insights into the multifaceted glutathione peroxidase (Gpx) superfamily. Antioxid Redox Signal. 2008;10(9):1501-14.
[6] Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A117a11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12(8):599-620.
[7] Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830-49.
[8] Hatem E, El Banna N, Huang ME. Multifaceted roles of glutathione and glutathione-based systems in carcinogenesis and anticancer drug resistance. Antioxid Redox Signal. 2017;27(15):1217-34.
[9] Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30(1-2):42-59.
[10] Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34(4):496-502.
[11] Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2):317-31.
[12] Combs JA, DeNicola GM. The non-essential amino acid cysteine becomes essential for tumor proliferation and survival. Cancers. 2019;11(5):678.
[13] Koppula P, Zhang Y, Zhuang L, Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun. 2018;38(1):12.
[14] Sharbeen G, McCarroll JA, Akerman A, Kopecky C, Youkhana J, Kokkinos J, et al. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition. Cancer Res. 2021;81(13):3461-79.
[15] Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88.
[16] Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem Sci. 2016;41(3):274-86.
[17] Salnikow K. Role of iron in cancer. Semin Cancer Biol. 2021;76:189-94.
[18] Torti SV, Torti FM. Iron and cancer: More ore to be mined. Nat Rev Cancer. 2013;13(5):342-55.
[19] Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14:507-15.
[20] Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest. 2018;128:3341-55.
[21] Wei R, Zhao Y, Wang J, Yang X, Li S, Wang Y, et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int J Biol Sci. 2021;17(11):2703-17.
[22] 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.
[23] 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.
[24] Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18(5):280-96.
[25] 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.
[26] Du Y, Guo Z. Recent progress in ferroptosis: inducers and inhibitors. Cell Death Discov. 2022;8:501.
[27] Leeya Y, Mulvany MJ, Queiroz EF, Marston A, Hostettmann K, Jansakul C. Hypotensive activity of an n-butanol extract and their purified compounds from leaves of Phyllanthus acidus (L.) skeels in rats. Eur J Pharmacol. 2010;649(1-3):301-13.
[28] Tan SP, Tan EN, Lim QY, Nafiah MA. Phyllanthus acidus (L.) skeels: a review of its traditional uses, phytochemistry, and pharmacological properties. J Ethnopharmacol. 2020;253:112610.
[29] Geng HC, Zhu HT, Wang D, Yang WN, Yang CR, Zhang YJ. Phyllanacidins aA-C, three new cleistanthane diterpenoids from Phyllanthus acidus and their cytotoxicities. Fitoterapia. 2021;148: 104793.
[30] Geng HC, Zhu HT, Yang WN, Wang D, Yang CR, Zhang YJ. New cytotoxic dichapetalins in the leaves of Phyllanthus acidus: Identification, quantitative analysis, and preliminary toxicity assessment. Bioorg Chem. 2021;114: 105125.
[31] Geng HC, Zhu HT, Yang WN, Wang D, Yang CR, et al. Phyllaciduloids E and F, two new cleistanthane diterpenoids from the leaves of Phyllanthus acidus. Nat Prod Res. 2022;36(20):5241-6.
[32] Sichaem J, Vo HC, Nha-Tran T, Jarupinthusophon S, Niamnont N, Srikittiwanna K, et al. 29-norlupane-1β-hydroxy-3,20-dione, a new norlupane triterpenoid from the twigs and leaves of Phyllanthus acidus. Nat Prod Res. 2021;35(20):3384-9.
[33] Xin Y, Xu J, Lv JJ, Zhu HT, Wang D, Yang CR, et al. Newent-kaurane and cleistanthane diterpenoids with potential cytotoxicity fromPhyllanthus acidus (L.) skeels. Fitoterapia. 2022;157:105133.
[34] Xin Y, Xu M, Wang YF, Zheng XH, Zhu HT, Wang D, et al. Phyllanthacidoid U: A new n-glycosyl norbisabolane sesquiterpene from Phyllanthus acidus (L.) Skeels. Nat Prod Res. 2021;35(21):3540-7.
[35] Zhang YJ, Abe T, Tanaka T, Yang CR, Kouno I. Phyllanemblinins A-F, new ellagitannins from Phyllanthus emblica. J Nat Prod. 2001;64(12):1527-32.
[36] Lv JJ, Yu S, Wang YF, Wang D, Zhu HT, Cheng RR, et al. Anti-hepatitis B virus norbisabolane sesquiterpenoids from Phyllanthus acidus and the establishment of their absolute configurations using theoretical calculations. J Org Chem. 2014;79(12):5432-47.
[37] Longuefosse JL, Nossin E. Medical ethnobotany survey in martinique. J Ethnopharmacol. 1996;53(3):117-42.
[38] Costa I, Barbosa DJ, Benfeito S, Silva V, Chavarria D, Borges F, et al. Molecular mechanisms of ferroptosis and their involvement in brain diseases. Pharmacol Ther. 2023;244: 108373.
[39] Kim HJ, Hwang KE, Park DS, Oh SH, Jun HY, Yoon KH, et al. Shikonin-induced necroptosis is enhanced by the inhibition of autophagy in non-small cell lung cancer cells. J Transl Med. 2017;15(1):123.
[40] Rochette L, Dogon G, Rigal E, Zeller M, Cottin Y, Vergely C. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci. 2022;24(1):449.
[41] Park MW, Cha HW, Kim J, Kim JH, Yang H, Yoon S, et al. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases. Redox Biol. 2021;41: 101947.
[42] Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165-76.
[43] Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease [J]. Nat Rev Mol Cell Biol. 2021;22(4):266-82.
[44] Xia H, Wu Y, Zhao J, Cheng C, Lin J, Yang Y, et al. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COP through recruiting YTHDF1 to facilitate the translation ofIREB2. Cell Death Differ. 2023;30(5):1293-304.
[45] Li Q, Liu H, Jin Y, Yu Y, Wang Y, Wu D, et al. Analysis of a new therapeutic target and construction of a prognostic model for breast cancer based on ferroptosis genes. Comput Biol Med. 2023;165: 107370.
[46] Tang Z, Ju Y, Dai X, Ni N, Liu Y, Zhang D, et al. HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration. Redox Biol. 2021;43: 101971.
[47] Zheng C, Zhang B, Li Y, Liu K, Wei W, Liang S, et al. Donafenib and GSK-J4 synergistically induce ferroptosis in liver cancer by upregulating HMOX1 expression. Adv Sci. 2023;10(22): e2206798.
[48] Liu Y, Lu S, Wu LL, Yang L, Yang L, Wang J. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023;14(8):519.
[49] Ouyang X, Zhu R, Lin L, Wang X, Zhuang Q, Hu D. GAPDH is a novel ferroptosis-related marker and correlates with immune microenvironment in lung adenocarcinoma. Metabolites. 2023;13(2):142.
[50] 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;32(7):687-90.
[51] Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381-96.
[52] Liu Y, Wu D, Fu Q, Hao S, Gu Y, Zhao W, et al. CHAC1 as a novel contributor of ferroptosis in retinal pigment epithelial cells with oxidative damage. Int J Mol Sci. 2023;24(2):1582.
[53] Nomura Y, Hirata Y, Kiuchi K, Oh-Hashi K. Translational and post-translational regulation of mouse cation transport regulator homolog 1. Sci Rep. 2016;6:28016.
[54] Chiang SK, Chen SE, Chang LC. A dual role of heme oxygenase-1 in cancer cells. Int J Mol Sci. 2018;20(1):39.
[55] Menon AV, Liu J, Tsai HP, Zeng L, Yang S, Asnani A, et al. Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease. Blood. 2022;139(6):936-41.
[56] Gottlieb Y, Truman M, Cohen LA, Leichtmann-Bardoogo Y, Meyron-Holtz EG. Endoplasmic reticulum anchored heme-oxygenase 1 faces the cytosol. Haematologica. 2012;97(10):1489-93.
[57] Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833(12):3460-70.
[58] Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89-102.
[59] Fujiki T, Ando F, Murakami K, Isobe K, Mori T, Susa K, et al. Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Sci Rep. 2019;9(1):9245.
[60] Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221-47.
[61] Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693-8.
[62] Eberhardt J, Santos-Martins D, Tillack AF, Forli S. Autodock Vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model. 2021;61(8):3891-8.
[63] Trott O, Olson AJ. Autodock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-61. |
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