Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells

Liang, Zheyong; Li, Wenjie; Liu, Jie; Li, Juan; He, Fang; Jiang, Yongchao; Lu, Yang; Li, Pingping; Wang, Bo; Wang, Yao-Chun; Ren, Yu; Yang, Jin Ming; Luo, Zhijun; Vaziri, Cyrus; Liu, Peijun

doi:10.1038/srep41776

Cited by 47 publications

(65 citation statements)

References 38 publications

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“…The aim of the present study was to test the effects of simvastatin on the growth of human lipoma cells derived from tumors with heterozygous mutations or deletions of PTEN. Simvastatin was selected for use as it has been demonstrated to exert anti-proliferative and growth-inhibitory actions on a number of cancer cell lines and tumor animal models (6,7,10,18,22,(26)(27)(28)(29)(30). In accordance with these results, the present study demonstrated that simvastatin reduced the viability of PTEN mutant lipoma cells by inducing apoptosis in a time-and dose-dependent manner.…”

Section: Discussionsupporting

confidence: 83%

Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells

et al. 2018

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Adipose tissue tumors (lipomas) frequently develop in patients with heterozygous germ line phosphatase and tensin homolog (PTEN) mutations. simvastatin has been demonstrated to exhibit antitumor effects, and so the aim of the present study was to assess the effects of simvastatin on the growth of human PTEN haploinsufficient lipoma cells. Whether the effects of simvastatin in lipomas are mediated via PTEN upregulation was also assessed. The results of the present study revealed that simvastatin treatment reduced cell viability and induced apoptosis in human lipoma cells. Furthermore, it was demonstrated that the expression of cellular PTEN mRNA and protein was increased following simvastatin stimulation. In addition, the phosphorylation of protein kinase B and downstream targets of mammalian target of rapamycin and 4E‑binding protein (4E‑BP)‑1 was attenuated. It was also demonstrated that simvastatin induced PTEN transcriptional upregulation by increasing peroxisome proliferator‑activated receptor (PPAR)γ expression. The small interfering RNA‑mediated knockdown of PPARγ abrogated the stimulatory effect of simvastatin on the PTEN protein, but did not influence apoptosis. The results of the present study suggest that simvastatin may be beneficial for patients with inoperable PTEN haploinsufficient lipomas.

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Section: Discussionsupporting

confidence: 83%

Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells

et al. 2018

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“…Furthermore, it has been shown that the suppression of MCM proteins makes cells hypersensitive to DNA replication stresses through increased frequency of chromosome breaks (Ibarra et al, 2008). Recently, it was demonstrated that Simvastatin can downregulate MCM7, which led to increased DNA damage and cell death (Liang et al, 2017). It would be interesting to combine MCM reducing drugs, like Simvastatin, with other DNA damaging agents, to therapeutically treat CCNE1-amplified HGSOC patients.…”

Section: Discussionmentioning

confidence: 99%

Replication stress induced by CCNE1 overexpression creates a dependency on XRCC2 at the replication fork

Doberstein

Karst

et al. 2018

Preprint

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Across multiple cancer types, genome instability has been linked to aberrant over-expression of CCNE1 due to premature cell cycle entry and replication stress. Using a gain-of-function screen, we found that XRCC2 cooperates with CCNE1 in the neoplastic transformation of TP53 mutant cells. A pan-cancer analysis of TCGA data revealed a striking correlation between CCNE1 and XRCC2 expression and knockdown of XRCC2 in Cyclin E1 overexpressing cell lines is synthetic lethal. Immunopurification of XRCC2 showed that it interacts with the Minichromosome Maintenance Complex Component 7 (MCM7) protein. This interaction appears to be critical for protecting replication forks as knockdown of XRCC2 leads to a strong increase in MCM7 ubiquitination with concomitant decrease in MCM7 protein levels, and reduced replication fork speed. Importantly, Overexpression of MCM7 rescues the effect of XRCC2 knockdown. Our data describe a new dependency of Cyclin E1 overexpressing tumors on factors that stabilize the replication fork.

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“…In fact, analyses have shown that in a molecular background where the tumor-suppressive retinoblastoma protein (pRb) axis is dysfunctional (eg, in SaOS2 osteosarcoma cells), the interference with the assembly of the minichromosome maintenance (MCM) complex and DNA replication causes more extensive DNA damages than in the presence of functional pRb (eg, in U2OS osteosarcoma cells). 42 Besides, premenopausal ER-positive breast cancer patients carrying a functional pRb are benefited from adjuvant tamoxifen treatment, in striking contrast to premenopausal ER-positive breast cancer patients with nonfunctional pRb, who do not experience any benefit. 43 Simvastatin negatively affects MCM7 expression, resulting in the elevation of the DNA damage marker, γH2AX.…”

Section: Introductionmentioning

confidence: 99%

Marketed drugs used for the management of hypercholesterolemia as anticancer armament

Papanagnou

Stivarou

Papageorgiou

et al. 2017

OTT

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The design of novel pharmacologic agents as well as their approval for sale in markets all over the world is a tedious and pricey process. Inevitably, oncologic patients commonly experience unwanted effects of new anticancer drugs, while the acquisition of clinical experience for these drugs is largely based on doctor–patient partnership which is not always effective. The repositioning of marketed non-antineoplastic drugs that hopefully exhibit anticancer properties into the field of oncology is a challenging option that gains ground and attracts preclinical and clinical research in an effort to override all these hindrances and minimize the risk for reduced efficacy and/or personalized toxicity. This review aims to present the anticancer properties of drugs used for the management of hypercholesterolemia. A global view of the antitumorigenicity of all marketed antihypercholesterolemic drugs is of major importance, given that atherosclerosis, which is etiologically linked to hypercholesterolemia, is a leading worldwide cause of morbidity and mortality, while hypercholesterolemia and tumorigenesis are known to be interrelated. In vitro, in vivo and clinical literature data accumulated so far outline the mechanistic basis of the antitumor function of these agents and how they could find application at the clinical setting.

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Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells

Cited by 47 publications

References 38 publications

Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells

Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells

Replication stress induced by CCNE1 overexpression creates a dependency on XRCC2 at the replication fork

Marketed drugs used for the management of hypercholesterolemia as anticancer armament

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