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Cited by 19Cancer, Lipids, and MetabolismFerroptosis and cancer prognosisCancer, Hypoxia, and Metabolism

Simvastatin Inhibits Endometrial Cancer Malignant Behaviors by Suppressing RAS/Mitogen-Activated Protein Kinase (MAPK) Pathway-Mediated Reactive Oxygen Species (ROS) and Ferroptosis

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Zhou, Dan, Wu, Qiuhua, Qiu, Huajuan, Li, Mi, Ji, Yanqin·2022·Evidence-Based Complementary and Alternative Medicine
DOI 10.1155/2022/6177477PMC PMC9586725
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Abstract

This paper was designed to explore the function of simvastatin as a chemotherapeutic drug on the endometrial cancer (EC) cell proliferation, invasion, and ferroptosis. Firstly, a number of in vitro experiments were conducted to determine the impact of different treatments of simvastatin on the Ishikawa cell invasion, proliferation, and colony formation. The concentration of DCFH-DA-labeled reactive oxygen species (ROS) in cells was assessed by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was performed to examine the intracellular contents of Fe2+, malondialdehyde (MDA), and glutathione (GSH). Additionally, Western blot was utilized to measure the expression level of RAS/mitogen-activated protein kinase (MAPK)-related proteins and ferroptosis-related proteins in cells. The results showed that simvastatin at 10 μM and 15 μM apparently suppressed the proliferation of Ishikawa cells, colony formation, and invasion ability of Ishikawa cells, and upregulated the level of MDA and ROS, but downregulated the level of GSH. Besides, 10 μM and 15 μM of simvastatin promoted cell ferroptosis (up-regulation of Fe2+ and TRF 1 protein level; down-regulation of SLC7A11 and FPN protein level) and lowered the RAS, p-MEK, and ERK protein level. Furthermore, experiments also revealed that the inhibitory effects of simvastatin on Ishikawa cell proliferation, colony formation, and invasion, as well as the promoting effects on oxidation and ferroptosis were reversed. All in all, simvastatin reduces the RAS/MAPK signaling pathway to inhibit Ishikawa cell proliferation, colony formation, and invasion, and promote cell oxidation and ferroptosis. This paper demonstrates the potential of simvastatin as a new anticancer drug for EC.

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  • SIM has inhibition effects on RAS/mitogen-activated protein kinase/ROS axis.

    “SIM has also been shown the inhibition effects on RAS/mitogen-activated protein kinase/ROS axis [77, 78].”

    From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [77]

    Results §3.4 reports that simvastatin inhibited RAS/MAPK signaling in Ishikawa cells. But the Discussion (§4) says simvastatin increased ROS levels in those cells, contrary to the claim that it inhibited the RAS/MAPK/ROS axis as a whole. Page numbers are not available in the supplied passages. (LLM, conf=0.87)

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  1. [1]Nagle C. M. Crosbie E. J. Brand A. The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer Gynecologic Oncology 2018 150 1 99 105 10.1016/j.ygyno.2018.04.006 2-s2.0-85046115551 29706522 · DOI
  2. [2]Bray F. Ferlay J. Soerjomataram I. Siegel R. L. Torre L. A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA: A Cancer Journal for Clinicians 2018 68 6 394 424 10.3322/caac.21492 2-s2.0-85053395052 30207593 · DOI · Paper page
  3. [3]Beavis A. L. Yen T. T. Stone R. L. Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: is there a role for chemotherapy? Gynecologic Oncology 2020 156 3 568 574 10.1016/j.ygyno.2019.12.028 31948730 PMC7388269 · DOI
  4. [4]Perera J. Hoskin P. Adjuvant therapy for high-risk endometrial carcinoma Clinical Oncology 2021 33 9 560 566 10.1016/j.clon.2021.05.009 34112584 · DOI
  5. [5]Arnold M. Pandeya N. Byrnes G. Global burden of cancer attributable to high body-mass index in 2012: a population-based study The Lancet Oncology 2015 16 1 36 46 10.1016/s1470-2045(14)71123-4 2-s2.0-84924910144 25467404 PMC4314462 · DOI
  6. [6]Stockwell B. R. Friedmann Angeli J. P. Bayir H. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease Cell 2017 171 2 273 285 10.1016/j.cell.2017.09.021 2-s2.0-85030552365 28985560 PMC5685180 · DOI · Paper page
  7. [7]Guan Z. Chen J. Li X. Dong N. Tanshinone IIA induces ferroptosis in gastric cancer cells through p53-mediated SLC7A11 down-regulation Bioscience Reports 2020 40 8 BSR20201807 10.1042/bsr20201807 PMC7953492 32776119 · DOI
  8. [8]Jiang X. Stockwell B. R. Conrad M. Ferroptosis: mechanisms, biology and role in disease Nature Reviews Molecular Cell Biology 2021 22 4 266 282 10.1038/s41580-020-00324-8 33495651 PMC8142022 · DOI
  9. [9]Zhang M. Zhang T. Song C. Guizhi fuling capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis Journal of Ethnopharmacology 2021 274 114064 10.1016/j.jep.2021.114064 33771639 · DOI
  10. [10]Wang H. Peng S. Cai J. Bao S. Silencing of PTPN18 induced ferroptosis in endometrial cancer cells through p-P38-mediated GPX4/xCT down-regulation Cancer Management and Research 2021 13 1757 1765 10.2147/cmar.s278728 33642877 PMC7903946 · DOI
  11. [11]Ge M. Niu J. Hu P. A ferroptosis-related signature robustly predicts clinical outcomes and associates with immune microenvironment for thyroid cancer Frontiers of Medicine 2021 8 637743 10.3389/fmed.2021.637743 PMC8076739 33928101 · DOI
  12. [12]Pedersen T. R. Tobert J. A. Simvastatin: a review Expert Opinion on Pharmacotherapy 2004 5 12 2583 2596 10.1517/14656566.5.12.2583 2-s2.0-10644224470 15571475 · DOI
  13. [13]Kitzmiller J. P. Sullivan D. M. Phelps M. A. Wang D. Sadee W. CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control Drug Metabolism and Drug Interactions 2013 28 1 59 63 10.1515/dmdi-2012-0031 2-s2.0-84876551991 23314529 PMC3681953 · DOI
  14. [14]Xia D. K. Hu Z. G. Tian Y. F. Zeng F. J. Statin use and prognosis of lung cancer: a systematic review and meta-analysis of observational studies and randomized controlled trials Drug Design, Development and Therapy 2019 13 405 422 10.2147/dddt.s187690 2-s2.0-85062726896 30774306 PMC6350654 · DOI
  15. [15]Cardwell C. R. Mc Menamin U. Hughes C. M. Murray L. J. Statin use and survival from lung cancer: a population-based cohort study Cancer Epidemiology, Biomarkers & Prevention 2015 24 5 833 841 10.1158/1055-9965.epi-15-0052 2-s2.0-84965106347 25934831 · DOI
  16. [16]Schnoll R. A. Johnson T. A. Lerman C. Genetics and smoking behavior Current Psychiatry Reports 2007 9 5 349 357 10.1007/s11920-007-0045-3 2-s2.0-35248867059 17915073 · DOI
  17. [17]Tate R. Zona E. De Cicco R. Simvastatin inhibits the expression of stemnessrelated genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton International Journal of Oncology 2017 51 6 1851 1859 10.3892/ijo.2017.4158 2-s2.0-85033438220 29039527 · DOI
  18. [18]Matsuo K. Hom M. S. Yabuno A. Association of statins, aspirin, and venous thromboembolism in women with endometrial cancer Gynecologic Oncology 2019 152 3 605 611 10.1016/j.ygyno.2018.12.020 2-s2.0-85059457948 30616901 PMC7526861 · DOI
  19. [19]Schointuch M. N. Gilliam T. P. Stine J. E. Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer Gynecologic Oncology 2014 134 2 346 355 10.1016/j.ygyno.2014.05.015 2-s2.0-84905584707 24880141 PMC4125536 · DOI
  20. [20]Li H. L. Fei X. M. Tang Y. Yang Y. L. Wang L. X. Geng J. W. Effect of doxycycline on intrinsic apoptosis of myeloma cell line H929 and its mechanism Zhongguo Shi Yan Xue Ye Xue Za Zhi 2022 30 2 441 448 10.19746/j.cnki.issn.1009-2137.2022.02.020 35395977 · DOI
  21. [22]Galluzzi L. Vitale I. Aaronson S. A. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018 Cell Death & Differentiation 2018 25 3 486 541 10.1038/s41418-017-0012-4 2-s2.0-85036533976 29362479 PMC5864239 · DOI · Paper page
  22. [23]Dillon M. Lopez A. Lin E. Sales D. Perets R. Jain P. Progress on Ras/MAPK signaling research and targeting in blood and solid cancers Cancers 2021 13 20 p. 5059 10.3390/cancers13205059 PMC8534156 34680208 · DOI
  23. [24]Vallianou N. G. Kostantinou A. Kougias M. Kazazis C. Statins and cancer Anti-Cancer Agents in Medicinal Chemistry 2014 14 5 706 712 10.2174/1871520613666131129105035 2-s2.0-84904472802 24295174 · DOI
  24. [25]Chushi L. Wei W. Kangkang X. Yongzeng F. Ning X. Xiaolei C. HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells Gene 2016 587 1 42 47 10.1016/j.gene.2016.04.029 2-s2.0-84964290587 27085483 · DOI
  25. [26]Kim J. S. Turbov J. Rosales R. Thaete L. G. Rodriguez G. C. Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth Gynecologic Oncology 2019 154 2 432 440 10.1016/j.ygyno.2019.05.022 2-s2.0-85066792418 31178149 · DOI
  26. [27]Menter D. G. Ramsauer V. P. Harirforoosh S. Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites PLoS One 2011 6 12 e28813 10.1371/journal.pone.0028813 2-s2.0-84055172757 PMC3245236 22216116 · DOI
  27. [28]Matusewicz L. Meissner J. Toporkiewicz M. Sikorski A. F. The effect of statins on cancer cells--review Tumor Biology 2015 36 7 4889 4904 10.1007/s13277-015-3551-7 2-s2.0-84938212167 26002574 · DOI
  28. [29]Saikolappan S. Kumar B. Shishodia G. Koul S. Koul H. K. Reactive oxygen species and cancer: a complex interaction Cancer Letters 2019 452 132 143 10.1016/j.canlet.2019.03.020 2-s2.0-85063536524 30905813 · DOI
  29. [30]Khan M. A. Chen H. C. Wan X. X. Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells Molecular Cell 2013 35 3 219 225 10.1007/s10059-013-2259-z 2-s2.0-84880036340 PMC3887918 23456297 · DOI
  30. [31]Buranrat B. Suwannaloet W. Naowaboot J. Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells Oncology Letters 2017 14 5 6243 6250 10.3892/ol.2017.6783 2-s2.0-85030163008 29113274 PMC5661424 · DOI
  31. [32]Wang Y. Xu S. L. Wu Y. Z. Simvastatin induces caspase-dependent apoptosis and activates P53 in OCM-1 cells Experimental Eye Research 2013 113 128 134 10.1016/j.exer.2013.05.013 2-s2.0-84879588683 23727160 · DOI
  32. [33]Tang R. Xu J. Zhang B. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity Journal of Hematology & Oncology 2020 13 1 p. 110 10.1186/s13045-020-00946-7 PMC7418434 32778143 · DOI
  33. [34]Sun X. Ou Z. Chen R. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells Hepatology 2016 63 1 173 184 10.1002/hep.28251 2-s2.0-84952639010 26403645 PMC4688087 · DOI · Paper page
  34. [35]He J. Ding H. Li H. Pan Z. Chen Q. Intra-tumoral expression of SLC7A11 is associated with immune microenvironment, drug resistance, and prognosis in cancers: a pan-cancer analysis Frontiers in Genetics 2021 12 770857 10.3389/fgene.2021.770857 PMC8687742 34938318 · DOI
  35. [36]Sehm T. Rauh M. Wiendieck K. Buchfelder M. Eyupoglu I. Y. Savaskan N. E. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis Oncotarget 2016 7 46 p. 74630 74647 10.18632/oncotarget.11858 2-s2.0-84996807781 PMC5342691 27612422 · DOI
  36. [37]Yang W. S. Stockwell B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells Chemistry & Biology 2008 15 3 234 245 10.1016/j.chembiol.2008.02.010 2-s2.0-40849085503 18355723 PMC2683762 · DOI · Paper page
  37. [39]Ye F. Chai W. Xie M. HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRAS(Q61L) cells American Journal of Cancer Research 2019 9 4 730 739 31105999 PMC6511643
  38. [40]Afrin S. Islam M. S. Patzkowsky K. Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells American Journal of Obstetrics and Gynecology 2020 223 5 p. 733.e1 733.e14 10.1016/j.ajog.2020.05.012 PMC7609626 32417359 · DOI

Cited by

Sorted by citations

Authors
Zhou, D., Wu, Q., Qiu, H., Li, M., & Ji, Y.
Affiliations
Huizhou Central People's Hospital (CN)
Corresponding author
Ji, Yanqin
ORCID
Venue
Evidence-Based Complementary and Alternative Medicine
Publisher
Wiley
Published
2022-10-14
Volume
2022
Pages
1-11
ISSN
  • 1741-427X (ISSN-L)
  • 1741-4288
DOI
10.1155/2022/6177477
PMC
PMC9586725
OpenAlex
W4306252826
Cited by
19
References
2
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 5
FWCI
1.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Evidence-based Complementary and Alternative Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
simvastatin, endometrial cancer, ferroptosis, RAS/MAPK pathway, reactive oxygen species, cell proliferation, cell invasion, Ishikawa cells, oxidative stress, SLC7A11, FPN, TRF1, malondialdehyde, glutathione, anticancer agents

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