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Cited by 43Cancer, Lipids, and MetabolismCancer-related Molecular PathwaysMicrotubule and mitosis dynamics

RETRACTED ARTICLE: Simvastatin and Atorvastatin inhibit DNA replication licensing factor MCM7 and effectively suppress RB-deficient tumors growth

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Li, Juan, Liu, Jie, Liang, Zheyong, He, Fang, Yang, Lu, Li, Pingping, Jiang, Yina, Wang, Bo +8 more·2017·Cell Death & Disease
DOI 10.1038/cddis.2017.46PMC PMC5386551
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Abstract

Loss or dysfunction of tumor suppressor retinoblastoma (RB) is a common feature in various tumors, and contributes to cancer cell stemness and drug resistance to cancer therapy. However, the strategy to suppress or eliminate Rb-deficient tumor cells remains unclear. In the present study, we accidentally found that reduction of DNA replication licensing factor MCM7 induced more apoptosis in RB-deficient tumor cells than in control tumor cells. Moreover, after a drug screening and further studies, we demonstrated that statin drug Simvastatin and Atorvastatin were able to inhibit MCM7 and RB expressions. Further study showed that Simvastatin and Atorvastatin induced more chromosome breaks and gaps of Rb-deficient tumor cells than control tumor cells. In vivo results showed that Simvastatin and Atorvastatin significantly suppressed Rb-deficient tumor growth than control in xenograft mouse models. The present work demonstrates that ‘old’ lipid-lowering drugs statins are novel weapons against RB-deficient tumors due to their effects on suppressing MCM7 protein levels.

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  • Simvastatin and atorvastatin downregulate MCM7 and RB expression.

    “certain statins, notably simvastatin and atorvastatin, have been shown to downregulate MCM7 and RB expression.”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [134]

  • Statins are linked to increased chromosomal abnormalities in RB-deficient tumor cells, suggesting potential application for treating RB-deficient tumors.

    “These statins have been linked to an increase in chromosomal abnormalities in RB-deficient tumor cells, hinting at their potential application for the treatment of RB-deficient tumors.134”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [134]

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References 61 · Cited by 43

Research works printed but not linked: 57

  1. Massague J. G1 cell-cycle control and cancer. Nature 2004; 432: 298–306. 15549091
  2. Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. Nat Rev Cancer 2008; 8: 714–724. 19143056 PMC2914856
  3. Lehn S, Ferno M, Jirstrom K, Ryden L, Landberg G. A non-functional retinoblastoma tumor suppressor (RB) pathway in premenopausal breast cancer is associated with resistance to tamoxifen. Cell Cycle 2011; 10: 956–962. 21358261
  4. Lin X, Li J, Yin G, Zhao Q, Elias D, Lykkesfeldt AE et al. Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties. Breast Cancer Res 2013; 15: R119. 24355041 PMC4057522
  5. Fragkos M, Ganier O, Coulombe P, Mechali M. DNA replication origin activation in space and time. Nat Rev Mol Cell Biol 2015; 16: 360–374. 25999062
  6. Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem 2002; 71: 333–374. 12045100
  7. Takahashi TS, Wigley DB, Walter JC. Pumps, paradoxes and ploughshares: mechanism of the MCM 2-7 DNA helicase. Trends Biochem Sci 2005; 30: 437–444. 16002295
  8. Woodward AM, Gohler T, Luciani MG, Oehlmann M, Ge X, Gartner A et al. Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol 2006; 173: 673–683. 16754955 PMC2063885
  9. Ge XQ, Jackson DA, Blow JJ. Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev 2007; 21: 3331–3341. 18079179 PMC2113033
  10. Ibarra A, Schwob E, Mendez J. Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc Natl Acad Sci USA 2008; 105: 8956–8961. 18579778 PMC2449346
  11. Gonzalez MA, Tachibana KE, Laskey RA, Coleman N. Control of DNA replication and its potential clinical exploitation. Nat Rev Cancer 2005; 5: 135–141. 15660109
  12. Jackson AP, Laskey RA, Coleman N. Replication proteins and human disease. Cold Spring Harb Perspect Biol 2014; 6: a013060. 23881941 PMC3941220
  13. Dudderidge TJ, Stoeber K, Loddo M, Atkinson G, Fanshawe T, Griffiths DF et al. Mcm2, Geminin, and KI67 define proliferative state and are prognostic markers in renal cell carcinoma. Clin Cancer Res 2005; 11: 2510–2517. 15814627
  14. Di Fiore R, D'Anneo A, Tesoriere G, Vento R. RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis. J Cell Physiol 2013; 228: 1676–1687. 23359405
  15. Knudsen ES, Knudsen KE. Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Exp Biol Med 2006; 231: 1271–1281. 16816134
  16. Bryant VL, Elias RM, McCarthy SM, Yeatman TJ, Alexandrow MG. Suppression of reserve MCM complexes chemosensitizes to gemcitabine and 5-Fluorouracil. Mol Cancer Res 2015; 13: 1296–1305. 26063742 PMC4573356
  17. Kang YH, Galal WC, Farina A, Tappin I, Hurwitz J. Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis. Proc Natl Acad Sci USA 2012; 109: 6042–6047. 22474384 PMC3341058
  18. Labib K, Tercero JA, Diffley JE. Uninterrupted MCM2-7 function required for DNA replication fork progression. Science 2000; 288: 1643–1647. 10834843
  19. Chuang CH, Wallace MD, Abratte C, Southard T, Schimenti JC. Incremental genetic perturbations to MCM2-7 expression and subcellular distribution reveal exquisite sensitivity of mice to DNA replication stress. PLoS Genet 2010; 6: e1001110. 20838603 PMC2936539
  20. Chuang CH, Yang D, Bai G, Freeland A, Pruitt SC, Schimenti JC. Post-transcriptional homeostasis and regulation of MCM2-7 in mammalian cells. Nucleic Acids Res 2012; 40: 4914–4924. 22362746 PMC3367205
  21. Holstein SA, Hohl RJ. Synergistic interaction of lovastatin and paclitaxel in human cancer cells. Mol Cancer Ther 2001; 1: 141–149. 12467231
  22. Feleszko W, Młynarczuk I, Olszewska D, Jalili A, Grzela T, Lasek W et al. Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis dependent mechanism. Int J Cancer 2002; 100: 111–118. 12115596
  23. Khanzada UK, Pardo OE, Meier C, Downward J, Seckl MJ, Arcaro A. Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signaling. Oncogene 2006; 25: 877–887. 16170339
  24. Sadeghi MM, Collinge M, Pardi R, Bender JR. Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein. J Immunol 2000; 165: 2712–2718. 10946302
  25. Liu P, Slater DM, Lenburg M, Nevis K, Cook JG, Vaziri C. Replication licensing promotes cyclin D1 expression and G1 progression in untransformed human cells. Cell Cycle 2009; 8: 125–136. 19106611 PMC3032797
  26. Darnel GA, Schroder WA, Antalis TM, Lambley E, Major L et al. Human papillomavirus E7 requires the protease Calpain to degrade the retinoblastoma protein. J Biol Chem 2007; 282: 37492–37500. 17977825
  27. Oh K-J, Kalinina A, Bagchi S. Destabilization of Rb by human papillomavirus E7 is cell cycle dependent: E2-25K is involved in the proteolysis. Virology 2010; 396: 118–124. 19906396 PMC2796474
  28. Wang J, Sampath A, Raychaudhuri P, Bagchi S. Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells. Oncogene 2001; 20: 4740–4749. 11498796
  29. Hamel PA, Gill RM, Phillips RA, Gallie BL. Regions controlling hyperphosphorylation and conformation of the retinoblastoma gene product are independent of domains required for transcriptional repression. Oncogene 1992; 7: 693–701. 1565466
  30. Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine depho-sphorylation of H2AX modulates apoptosis and survival decisions. Nature 2009; e458: 591–596. PMC2692521 19234442
  31. Banath JP, Klokov D, MacPhail SH, Banuelos CA, Olive PL. Residual gammaH2AX foci as an indication of lethal DNA lesions. BMC Cancer 2010; 10: 4. 20051134 PMC2819996
  32. Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer 2016; 16: 20–33. 26678314
  33. Al-Ejeh F, Kumar R, Wiegmans A, Lakhani SR, Brown MP, Khanna KK. Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes. Oncogene 2010; 29: 6085–6098. 20818418
  34. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 2008; 8: 193–204. 18256616
  35. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y et al. Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 2006; 114: 2655–2662. 17116771
  36. Ma L, Niknejad N, Gorn-Hondermann I, Dayekh K, Dimitroulakos J. Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells. PLoS ONE 2012; 7: e46055. 23029387 PMC3460930
  37. Chen JC, Wu ML, Huang KC, Lin WW. HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression. Cardiovasc Res 2008; 80: 138–150. 18556704
  38. Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 2010; 70: 7699–7709. 20876807
  39. Roudier E, Mistafa O, Stenius U. Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs. Mol Cancer Ther 2006; 5: 2706–2715. 17121917
  40. Muñoz N, Bosch FX. The causal link between HPV and cervical cancer and its implications for prevention of cervical cancer. Bull Pan Am Health Organ 1996; 30: 362–377. 9041748
  41. Zhai K, Ding J, Shi HZ. HPV and lung cancer risk: a meta-analysis. J Clin Virol 2015; 63: 84–90. 25315992
  42. Betteridge DJ, Carmena R. The diabetogenic action of statins-mechanisms and clinical implications. Nat Rev Endocrinol 2016; 12: 99–110. 26668119
  43. Armitage J. The safety of statins in clinical practice. Lancet 2007; 70: 1781–1790. 17559928
  44. Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer 2005; 5: 930–942. 16341084
  45. Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS et al. Statins and the risk of colorectal cancer. N Engl J Med 2005; 352: 2184–2192. 15917383
  46. Collisson EA, Kleer C, Wu M, De A, Gambhir SS, Merajver SD et al. Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells. Mol Cancer Ther 2003; 2: 941–948. 14578459 PMC4161126
  47. Lee SJ, Lee I, Lee J, Park C, Kang WK. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90alpha in human colorectal cancer. Br J Cancer 2014; 111: 497–505. 24945998 PMC4119970
  48. Li T, Wang D, Tian Y, Yu H, Wang Y, Quan W et al. Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci 2014; 341: 88–96. 24774750
  49. Kunnev D, Rusiniak ME, Kudla A, Freeland A, Cady GK, Pruitt SC. DNA damage response and tumorigenesis in Mcm2-deficient mice. Oncogene 2010; 29: 3630–3638. 20440269 PMC2892019
  50. Gopalan A, Yu W, Sanders BG, Kline K. Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett 2013; 328: 285–296. 23063651
  51. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 2010; 9: 4153–4163. 20948315 PMC3055199
  52. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 2001; 276: 42462–42467. 11571274
  53. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012; 12: 801–817. 23175119
  54. Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 2016; 16: 35–42. 26667849
  55. Shima N, Alcaraz A, Liachko I, Buske TR, Andrews CA, Munroe RJ et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet 2007; 39: 93–98. 17143284
  56. Kawabata T, Luebben SW, Yamaguchi S, Ilves I, Matise I, Buske T et al. Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression. Mol Cell 2011; 41: 543–553. 21362550 PMC3062258
  57. Luebben SW, Kawabata T, Johnson CS, O'Sullivan MG, Shima N. A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression. Nucleic Acids Res 2014; 42: 5605–5615. 24589582 PMC4027174

Authors
Li, J., Liu, J., Liang, Z., He, F., Yang, L., Li, P., Jiang, Y., Wang, B., Zhou, C., Wang, Y., Ren, Y., Yang, J., Zhang, J., Luo, Z., Vaziri, C., & Liu, P.
Affiliations
  • First Affiliated Hospital of Xi'an Jiaotong University (CN)
  • Roswell Park Comprehensive Cancer Center (US)
  • Boston University (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Liu, Peijun
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2017-03-16
Volume
8
Issue
3
Pages
e2673-e2673
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2017.46
PMC
PMC5386551
OpenAlex
W2597322588
Cited by
43
References
61
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 1 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 7 · 2017: 3
FWCI
1.56
Type
journal article
Language
en
Status
Retracted
Update notices
retraction (2025-11-27)
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81071876, 81272342, NCET-10)
  • Program for New Century Excellent Talents in University (NCET-10)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
simvastatin, atorvastatin, statins, MCM7, retinoblastoma protein, DNA replication licensing, apoptosis, chromosome breakage, tumor growth inhibition, lipid-lowering drugs, cancer therapy
MeSH terms
Atorvastatin, Animals, Cell Line, DNA Replication, Humans, Retinoblastoma, Retinoblastoma Protein, Cell Cycle Proteins, Simvastatin, Cell Line, Tumor, Cell Proliferation, Mice, Minichromosome Maintenance Complex Component 7

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