Artesunate Inhibits the Growth of Insulinoma Cells via SLC7A11/ GPX4-mediated Ferroptosis


Cite item

Full Text

Abstract

Background:Artesunate (ART) has been recognized to induce ferroptosis in various tumor phenotypes, including neuroendocrine tumors. We aimed to investigate the effects of ART on insulinoma and the underlying mechanisms by focusing on the process of ferroptosis.

Methods:The CCK8 and colony formation assays were conducted to assess the effectiveness of ART. Lipid peroxidation, glutathione, and intracellular iron content were determined to validate the process of ferroptosis, while ferrostatin-1 (Fer-1) was employed as the inhibitor of ferroptosis. Subcutaneous tumor models were established and treated with ART. The ferroptosis-associated proteins were determined by western blot and immunohistochemistry assays. Pathological structures of the liver were examined by hematoxylin-eosin staining.

Results:ART suppressed the growth of insulinoma both in vitro and in vivo. Insulinoma cells treated by ART revealed signs of ferroptosis, including increased lipid peroxidation, diminished glutathione levels, and ascending intracellular iron. Notably, ART-treated insulinoma cells exhibited a decline in the expressions of catalytic component solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). These alterations were negated by Fer-1. Moreover, no hepatotoxicity was observed upon the therapeutic dose of ART.

Conclusion:Artesunate might regulate ferroptosis of insulinoma cells through the SLC7A11/GPX4 pathway.

About the authors

Fengping Chen

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Jiexia Lu

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Biaolin Zheng

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Nan Yi

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Chunxiao Xie

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Feiran Chen

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Dafu Wei

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Email: info@benthamscience.net

Haixing Jiang

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Author for correspondence.
Email: info@benthamscience.net

Shanyu Qin

Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Hofland J, Kaltsas G, de Herder WW. Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms. Endocr Rev 2020; 41(2): 371-403. doi: 10.1210/endrev/bnz004 PMID: 31555796
  2. Liu Q, Duan J, Zheng Y, Luo J, Cai X, Tan H. Rare malignant insulinoma with multiple liver metastases derived from ectopic pancreas: 3-year follow-up and literature review. OncoTargets Ther 2018; 11: 1813-9. doi: 10.2147/OTT.S154991 PMID: 29662318
  3. Crinò SF, Partelli S, Napoleon B, et al. Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma. Dig Liver Dis 2023; 55(9): 1187-93. doi: 10.1016/j.dld.2023.06.021 PMID: 37407318
  4. Jilesen APJ, van Eijck CHJ, in’t Hof KH, van Dieren S, Gouma DJ, van Dijkum EJMN. Postoperative complications, in-hospital mortality and 5-year survival after surgical resection for patients with a pancreatic neuroendocrine tumor: A systematic review. World J Surg 2016; 40(3): 729-48. doi: 10.1007/s00268-015-3328-6 PMID: 26661846
  5. El Sayed G, Frim L, Franklin J, et al. Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: A systematic literature review. Therap Adv Gastroenterol 2021; 14: 17562848211042171. doi: 10.1177/17562848211042171 PMID: 34819995
  6. Crinò SF, Napoleon B, Facciorusso A, et al. Endoscopic ultrasound-guided radiofrequency ablation versus surgical resection for treatment of pancreatic insulinoma. Clin Gastroenterol Hepatol 2023; 1542-3565. doi: 10.1016/j.cgh.2023.02.022
  7. Choi JH, Seo DW, Song TJ, et al. Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors. Endoscopy 2018; 50(11): 1099-104. doi: 10.1055/a-0583-8387 PMID: 29727904
  8. Marx M, Godat S, Caillol F, et al. Management of non-functional pancreatic neuroendocrine tumors by endoscopic ultrasound-guided radiofrequency ablation: Retrospective study in two tertiary centers. Dig Endosc 2022; 34(6): 1207-13. doi: 10.1111/den.14224 PMID: 34963025
  9. Magi L, Marasco M, Rinzivillo M, Faggiano A, Panzuto F. Management of functional pancreatic neuroendocrine neoplasms. Curr Treat Options Oncol 2023; 24(7): 725-41. doi: 10.1007/s11864-023-01085-0 PMID: 37103745
  10. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5): 1060-72. doi: 10.1016/j.cell.2012.03.042 PMID: 22632970
  11. Yu P, Zhang J, Ding Y, et al. Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation. Hum Cell 2022; 35(3): 836-48. doi: 10.1007/s13577-022-00682-9 PMID: 35212945
  12. Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22(4): 266-82. doi: 10.1038/s41580-020-00324-8 PMID: 33495651
  13. Gong Y, Wang N, Liu N, Dong H. Lipid peroxidation and GPX4 inhibition are common causes for myofibroblast differentiation and ferroptosis. DNA Cell Biol 2019; 38(7): 725-33. doi: 10.1089/dna.2018.4541 PMID: 31140862
  14. Xu T, Ding W, Ji X, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 2019; 23(8): 4900-12. doi: 10.1111/jcmm.14511 PMID: 31232522
  15. Ye Z, Chen H, Ji S, et al. MEN1 promotes ferroptosis by inhibiting mTOR-SCD1 axis in pancreatic neuroendocrine tumors. Acta Biochim Biophys Sin 2022; 54(11): 1599-609. doi: 10.3724/abbs.2022162 PMID: 36604142
  16. Ye M, Lu F, Chen J, et al. Orlistat induces ferroptosis in pancreatic neuroendocrine tumors by inactivating the MAPK pathway. J Cancer 2023; 14(8): 1458-69. doi: 10.7150/jca.83118 PMID: 37283794
  17. Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol 2020; 28: 101328. doi: 10.1016/j.redox.2019.101328 PMID: 31574461
  18. Augustin Y, Staines HM, Krishna S. Artemisinins as a novel anti- cancer therapy: Targeting a global cancer pandemic through drug repurposing. Pharmacol Ther 2020; 216: 107706. doi: 10.1016/j.pharmthera.2020.107706 PMID: 33075360
  19. Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017; 46: 65-83. doi: 10.1016/j.semcancer.2017.02.009 PMID: 28254675
  20. Zhao F, Vakhrusheva O, Markowitsch SD, et al. Artesunate impairs growth in cisplatin-resistant bladder cancer cells by cell cycle arrest, apoptosis and autophagy induction. Cells 2020; 9(12): 2643. doi: 10.3390/cells9122643 PMID: 33316936
  21. Song Q, Peng S, Che F, Zhu X. Artesunate induces ferroptosis via modulation of p38 and ERK signaling pathway in glioblastoma cells. J Pharmacol Sci 2022; 148(3): 300-6. doi: 10.1016/j.jphs.2022.01.007 PMID: 35177209
  22. Yan G, Dawood M, Böckers M, et al. Multiple modes of cell death in neuroendocrine tumors induced by artesunate. Phytomedicine 2020; 79: 153332. doi: 10.1016/j.phymed.2020.153332 PMID: 32957040
  23. Hu P, Ni C, Teng P. Effects of artesunate on the malignant biological behaviors of non-small cell lung cancer in human and its mechanism. Bioengineered 2022; 13(3): 6590-9. doi: 10.1080/21655979.2022.2042141 PMID: 35361045
  24. Huang Z, Gan S, Zhuang X, et al. Artesunate inhibits the cell growth in colorectal cancer by promoting ros-dependent cell senescence and autophagy. Cells 2022; 11(16): 2472. doi: 10.3390/cells11162472 PMID: 36010550
  25. Li Z, Dai H, Huang X, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin 2021; 42(2): 301-10. doi: 10.1038/s41401-020-0478-3 PMID: 32699265
  26. Markowitsch SD, Schupp P, Lauckner J, et al. Artesunate inhibits growth of sunitinib-resistant renal cell carcinoma cells through cell cycle arrest and induction of ferroptosis. Cancers 2020; 12(11): 3150. doi: 10.3390/cancers12113150 PMID: 33121039
  27. Cao D, Chen D, Xia JN, et al. Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation. Biomed Pharmacother 2022; 155: 113705. doi: 10.1016/j.biopha.2022.113705 PMID: 36271541
  28. Hänninen MM, Haapasalo J, Haapasalo H, et al. Expression of iron-related genes in human brain and brain tumors. BMC Neurosci 2009; 10(1): 36. doi: 10.1186/1471-2202-10-36 PMID: 19386095
  29. Boult J, Roberts K, Brookes MJ, et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008; 14(2): 379-87. doi: 10.1158/1078-0432.CCR-07-1054 PMID: 18223212
  30. Calzolari A, Oliviero I, Deaglio S, et al. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis 2007; 39(1): 82-91. doi: 10.1016/j.bcmd.2007.02.003 PMID: 17428703
  31. Huang X. Iron overload and its association with cancer risk in humans: Evidence for iron as a carcinogenic metal. Mutat Res 2003; 533(1-2): 153-71. doi: 10.1016/j.mrfmmm.2003.08.023 PMID: 14643418
  32. Oh S, Kim BJ, Singh NP, Lai H, Sasaki T. Synthesis and anti- cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide. Cancer Lett 2009; 274(1): 33-9. doi: 10.1016/j.canlet.2008.08.031 PMID: 18838215
  33. Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 2017; 11: 254-62. doi: 10.1016/j.redox.2016.12.010 PMID: 28012440
  34. Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: Insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med 2013; 65: 1174-94. doi: 10.1016/j.freeradbiomed.2013.09.001 PMID: 24036104
  35. Lane DJR, Merlot AM, Huang MLH, et al. Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease. Biochim Biophys Acta Mol Cell Res 2015; 1853(5): 1130-44. doi: 10.1016/j.bbamcr.2015.01.021 PMID: 25661197
  36. Coffey R, Ganz T. Iron homeostasis: An anthropocentric perspective. J Biol Chem 2017; 292(31): 12727-34. doi: 10.1074/jbc.R117.781823 PMID: 28615456
  37. Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 2021; 11(7): 3052-9. doi: 10.7150/thno.54113 PMID: 33537073
  38. Xie Y, Hou W, Song X, et al. Ferroptosis: Process and function. Cell Death Differ 2016; 23(3): 369-79. doi: 10.1038/cdd.2015.158 PMID: 26794443
  39. Wei S, Liu L, Chen Z, et al. Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence. J Cell Mol Med 2020; 24(1): 276-84. doi: 10.1111/jcmm.14717 PMID: 31746143
  40. Ilett KF, Ethell BT, Maggs JL, et al. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos 2002; 30(9): 1005-12. doi: 10.1124/dmd.30.9.1005 PMID: 12167566
  41. Song X, Zhu S, Chen P, et al. AMPK-Mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc– activity. Curr Biol 2018; 28(15): 2388-2399.e5. doi: 10.1016/j.cub.2018.05.094 PMID: 30057310
  42. Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA. Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance. Crit Rev Oncol Hematol 2020; 155: 103095. doi: 10.1016/j.critrevonc.2020.103095 PMID: 32927333
  43. Li Q, Peng F, Yan X, et al. Inhibition of SLC7A11-GPX4 signal pathway is involved in aconitine-induced ferroptosis in vivo and in vitro. J Ethnopharmacol 2023; 303: 116029. doi: 10.1016/j.jep.2022.116029 PMID: 36503029
  44. Guo S, Zhao W, Zhang W, Li S, Teng G, Liu L. Vitamin D promotes ferroptosis in colorectal cancer stem cells via SLC7A11 downregulation. Oxid Med Cell Longev 2023; 2023: 1-16. doi: 10.1155/2023/4772134 PMID: 36846715
  45. Guan X, Li Z, Zhu S, et al. Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils. Life Sci 2021; 264: 118660. doi: 10.1016/j.lfs.2020.118660 PMID: 33127512
  46. Yuan Y, Zhai Y, Chen J, Xu X, Wang H. Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 axis. Biomolecules 2021; 11(7): 923. doi: 10.3390/biom11070923 PMID: 34206421

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers