Simvastatin is effective in killing the radioresistant breast carcinoma cells.
Autophagic Cell Death
/ drug effects
Breast Neoplasms
/ pathology
Cadherins
/ metabolism
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Survival
/ drug effects
Epithelial-Mesenchymal Transition
Female
Humans
Hydroxymethylglutaryl CoA Reductases
/ metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/ pharmacology
Radiation Tolerance
/ drug effects
Radiation-Sensitizing Agents
/ pharmacology
Simvastatin
/ pharmacology
Up-Regulation
breast cancer cells
cancer stem cells
migration
radiotherapy
simvastatin
Journal
Radiology and oncology
ISSN: 1581-3207
Titre abrégé: Radiol Oncol
Pays: Poland
ID NLM: 9317213
Informations de publication
Date de publication:
04 05 2021
04 05 2021
Historique:
received:
10
03
2021
accepted:
02
04
2021
pubmed:
4
5
2021
medline:
21
9
2021
entrez:
3
5
2021
Statut:
epublish
Résumé
Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive. Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines. Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased. The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes.
Sections du résumé
BACKGROUND
Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive.
MATERIALS AND METHODS
Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines.
RESULTS
Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased.
CONCLUSIONS
The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes.
Identifiants
pubmed: 33939900
pii: raon-2021-0020
doi: 10.2478/raon-2021-0020
pmc: PMC8366725
doi:
Substances chimiques
Cadherins
0
Hydroxymethylglutaryl-CoA Reductase Inhibitors
0
Radiation-Sensitizing Agents
0
Simvastatin
AGG2FN16EV
HMGCR protein, human
EC 1.1.1.-
Hydroxymethylglutaryl CoA Reductases
EC 1.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
305-316Informations de copyright
© 2021 Bertram Aschenbrenner, Giulia Negro, Dragana Savic, Maxim Sorokin, Anton Buzdin, Ute Ganswindt, Maja Cemazar, Gregor Sersa, Sergej Skvortsov, Ira Skvortsova, published by Sciendo.
Références
EU Science Hub. 2020 Cancer incidence and mortality in EU-27 countries. [Internet]. [cited 2021 Jan 22]. Available at: https://ec.europa.eu/jrc/en/news/2020-cancer-incidence-and-mortality-eu-27-countries
Thomas MA, Ochoa LL, Zygmunt TM, Matesa M, Altman MB, Garcia-Ramirez JL, et al. Accelerated partial breast irradiation: a safe, effective, and convenient early breast cancer treatment option. Mo Med 2015; 112: 379-84. PMID: 26606820
Merino T, Tran WT, Czarnota GJ. Re-irradiation for locally recurrent refractory breast cancer. Oncotarget 2015; 6: 35051-62. doi: 10.18632/onco-target.6036
doi: 10.18632/onco-target.6036
Siglin J, Champ CE, Vakhnenko Y, Anne PR, Simone NL. Radiation therapy for locally recurrent breast cancer. Int J Breast Cancer 2012; 2012: 571946. doi: 10.1155/2012/571946
doi: 10.1155/2012/571946
Fredriksson I, Liljegren G, Arnesson L-G, Emdin SO, Palm-Sjövall M, Fornander T, et al. Local recurrence in the breast after conservative surgery − a study of prognosis and prognostic factors in 391 women. Eur J Cancer 2002; 38: 1860-70. doi: 10.1016/s0959-8049(02)00219-8
doi: 10.1016/s0959-8049(02)00219-8
Alpert TE, Kuerer HM, Arthur DW, Lannin DR, Haffty BG. Ipsilateral breast tumor recurrence after breast conservation therapy: outcomes of salvage mastectomy vs. salvage breast-conserving surgery and prognostic factors for salvage breast preservation. Int J Radiat Oncol Biol Phys 2005; 63: 845-51. doi: 10.1016/j.ijrobp.2005.02.035
doi: 10.1016/j.ijrobp.2005.02.035
Huang E, Buchholz TA, Meric F, Krishnamurthy S, Mirza NQ, Ames FC, et al. Classifying local disease recurrences after breast conservation therapy based on location and histology: new primary tumors have more favorable outcomes than true local disease recurrences. Cancer 2002; 95: 2059-67. doi: 10.1002/cncr.10952
doi: 10.1002/cncr.10952
Bedwinek J. Natural history and management of isolated local-regional recurrence following mastectomy. Semin Radiat Oncol 1994; 4: 260-9. doi: 10.1053/SRAO00400260
doi: 10.1053/SRAO00400260
Belkacemi Y, Hanna NE, Besnard C, Majdoul S, Gligorov J. Local and regional breast cancer recurrences: salvage therapy options in the new era of molecular subtypes. Front Oncol 2018; 8: 112. doi: 10.3389/fonc.2018.00112
doi: 10.3389/fonc.2018.00112
Matusewicz L, Czogalla A, Sikorski AF. Attempts to use statins in cancer therapy: an update. Tumor Biol 2020; 42: 1010428320941760. doi: 10.1177/1010428320941760
doi: 10.1177/1010428320941760
Skvortsova I, Skvortsov S, Popper BA, Haidenberger A, Saurer M, Gunkel AR, et al. Rituximab enhances radiation-triggered apoptosis in Non-Hodgkin’s lymphoma cells via caspase-dependent and-independent mechanisms. J Radiat Res 2006; 47: 183-96. doi: 10.1269/jrr.47.183
doi: 10.1269/jrr.47.183
Skvortsova I, Skvortsov S, Haidenberger A, Devries A, Nevinny-Stickel M, Saurer M, et al. Effects of paclitaxel and docetaxel on EGFR-expressing human carcinoma cells under normoxic versus hypoxic conditions in vitro. J Chemother 2004; 16: 372-80. doi: 10.1179/joc.2004.16.4.372
doi: 10.1179/joc.2004.16.4.372
Skvortsov S, Sarg B, Lindner H, Lukas P, Hilbe W, Zwierzina H, et al. Cetuximab inhibits thymidylate synthase in colorectal cells expressing epidermal growth factor receptor. Proteomics Clin Appl 2008; 2: 908-14. doi: 10.1002/prca.200780034
doi: 10.1002/prca.200780034
Choi J, Yoon YN, Kim N, Park CS, Seol H, Park I-C, et al. Predicting radiation resistance in breast cancer with expression status of phosphorylated S6K1. Sci Rep 2020; 10: 641. doi: 10.1038/s41598-020-57496-8
doi: 10.1038/s41598-020-57496-8
Garcia-Estevez L, Moreno-Bueno G. Updating the role of obesity and cholesterol in breast cancer. Breast Cancer Res 2019; 21: 35. doi: 10.1186/s13058-019-1124-1
doi: 10.1186/s13058-019-1124-1
Hirata E, Sahai E. Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med 2017; 7: a026781. doi: 10.1101/cshperspect.a026781
doi: 10.1101/cshperspect.a026781
Bjarnadottir O, Feldt M, Inasu M, Bendahl PO, Elebro K, Kimbung S, et al. Statin use, HMGCR expression, and breast cancer survival - The Malmo Diet and Cancer Study. Sci Rep 2020; 10: 558. doi: 10.1038/s41598-019-57323-9
doi: 10.1038/s41598-019-57323-9
Arnold CR, Mangesius J, Skvortsova II, Ganswindt U. The role of cancer stem cells in radiation resistance. Front Oncol 2020; 10: 164. doi: 10.3389/fonc.2020.00164
doi: 10.3389/fonc.2020.00164
Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova I-I. Therapy resistance mediated by cancer stem cells. Semin Cancer Biol 2018; 53: 156-67. doi: 10.1016/j.semcancer.2018.11.006
doi: 10.1016/j.semcancer.2018.11.006
Steinbichler TB, Savic D, Dudás J, Kvitsaridze I, Skvortsov S, Riechelmann H, et al. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol 2020; 60: 148-56. doi: 10.1016/j.semcancer.2019.09.007
doi: 10.1016/j.semcancer.2019.09.007
Wu QJ, Tu C, Li YY, Zhu J, Qian KQ, Li WJ, et al. Statin use and breast cancer survival and risk: a systematic review and meta-analysis. Oncotarget 2015; 6: 42988-3004. doi: 10.18632/oncotarget.5557
doi: 10.18632/oncotarget.5557
Efimova E V, Ricco N, Labay E, Mauceri HJ, Flor AC, Ramamurthy A, et al. HMG-CoA reductase inhibition delays DNA repair and promotes senescence after tumor irradiation. Mol Cancer Ther 2018; 17: 407-18. doi: 10.1158/1535-7163.MCT-17-0288
doi: 10.1158/1535-7163.MCT-17-0288
Longo J, van Leeuwen JE, Elbaz M, Branchard E, Penn LZ. Statins as anticancer agents in the era of precision medicine. Clin Cancer Res 2020; 26: 5791-800. doi: 10.1158/1078-0432.CCR-20-1967
doi: 10.1158/1078-0432.CCR-20-1967
Kaplan-Meier Plotter. Breast cancer. [Internet]. [cited 2021 Jan 22]. Available at: https://kmplot.com/analysis/
Ricco N, Flor A, Wolfgeher D, Efimova EV, Ramamurthy A, Appelbe OK, et al. Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer. Mol Oncol 2019; 13: 1927-43. doi: 10.1002/1878-0261.12535
doi: 10.1002/1878-0261.12535
Wolfe AR, Debeb BG, Lacerda L, Larson R, Bambhroliya A, Huang X, et al. Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat 2015; 154: 495-508. doi: 10.1007/s10549-015-3645-3
doi: 10.1007/s10549-015-3645-3
Wolfe AR, Woodward WA. Breast cancer stem cell correlates as predicative factors for radiation therapy. Semin Radiat Oncol 2015; 25: 251-9. doi: 10.1016/j.semradonc.2015.05.009
doi: 10.1016/j.semradonc.2015.05.009
Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: a review. Breast Cancer 2017; 9: 559-65. doi: 10.2147/BCTT.S148080
doi: 10.2147/BCTT.S148080
Rahal OM, Woodward WA. Cholesterol and radiosensitivity. Curr Breast Cancer Rep 2016; 8: 32-9. doi: 10.1007/s12609-016-0202-y
doi: 10.1007/s12609-016-0202-y
Jin Y, Xu K, Chen Q, Wang B, Pan J, Huang S, et al. Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway. Exp Cell Res 2018; 362: 362-9. doi: 10.1016/j.yexcr.2017.11.037
doi: 10.1016/j.yexcr.2017.11.037
Xie F, Liu J, Li C, Zhao Y. Simvastatin blocks TGF-β1-induced epithelial-mesenchymal transition in human prostate cancer cells. Oncol Lett 2016; 11: 3377-83. doi: 10.3892/ol.2016.4404
doi: 10.3892/ol.2016.4404
Kato S, Liberona MF, Cerda-Infante J, Sánchez M, Henríquez J, Bizama C, et al. Simvastatin interferes with cancer “stem-cell” plasticity reducing metastasis in ovarian cancer. Endocr Relat Cancer 2018; 25: 821-36. doi: 10.1530/ERC-18-0132
doi: 10.1530/ERC-18-0132
Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, et al. Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 2011; 103: 1461-8. doi: 10.1093/jnci/djr291
doi: 10.1093/jnci/djr291
Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: a systematic review and meta-analysis. Int J cancer 2016; 139: 1281-8. doi: 10.1002/ijc.30185
doi: 10.1002/ijc.30185
Bhutia SK, Mukhopadhyay S, Sinha N, Das DN, Panda PK, Patra SK, et al. Autophagy: cancer’s friend or foe? Adv Cancer Res 2013; 118: 61-95. doi: 10.1016/B978-0-12-407173-5.00003-0
doi: 10.1016/B978-0-12-407173-5.00003-0