Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1

Rusin, Marek; Zajkowicz, Artur; Butkiewicz, Dorota

doi:10.1016/j.mad.2009.06.005

Cited by 50 publications

(44 citation statements)

References 42 publications

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“…WRN interacts with BRCA1 in response to interstrand crosslinks; BRCA1 can stimulate both WRN exonuclease and helicase activity in vitro [44]; WRN interacts with BRCA1 at telomeres of U-2 OS ALT cells in response to resveratrol treatment [49]. BRCA1 is also implicated in telomere maintenance as BRCA1 deficiency results in telomere loss and telomere dysfunction in T-cells [50].…”

Section: Discussionmentioning

confidence: 99%

WRN Loss Induces Switching of Telomerase-Independent Mechanisms of Telomere Elongation

2014

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Telomere maintenance can occur in the presence of telomerase or in its absence, termed alternative lengthening of telomeres (ALT). ALT adds telomere repeats using recombination-based processes and DNA repair proteins that function in homologous recombination. Our previous work reported that the RecQ-like BLM helicase is required for ALT and that it unwinds telomeric substrates in vitro. WRN is also a RecQ-like helicase that shares many biochemical functions with BLM. WRN interacts with BLM, unwinds telomeric substrates, and co-localizes to ALT-associated PML bodies (APBs), suggesting that it may also be required for ALT processes. Using long-term siRNA knockdown of WRN in three ALT cell lines, we show that some, but not all, cell lines require WRN for telomere maintenance. VA-13 cells require WRN to prevent telomere loss and for the formation of APBs; Saos-2 cells do not. A third ALT cell line, U-2 OS, requires WRN for APB formation, however WRN loss results in p53-mediated apoptosis. In the absence of WRN and p53, U-2 OS cells undergo telomere loss for an intermediate number of population doublings (50–70), at which point they maintain telomere length even with the continued loss of WRN. WRN and the tumor suppressor BRCA1 co-localize to APBs in VA-13 and U-2 OS, but not in Saos-2 cells. WRN loss in U-2 OS is associated with a loss of BRCA1 from APBs. While the loss of WRN significantly increases telomere sister chromatid exchanges (T-SCE) in these three ALT cell lines, loss of both BRCA1 and WRN does not significantly alter T-SCE. This work demonstrates that ALT cell lines use different telomerase-independent maintenance mechanisms that variably require the WRN helicase and that some cells can switch from one mechanism to another that permits telomere elongation in the absence of WRN. Our data suggest that BRCA1 localization may define these mechanisms.

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Section: Discussionmentioning

confidence: 99%

WRN Loss Induces Switching of Telomerase-Independent Mechanisms of Telomere Elongation

2014

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“…Resveratrol can alter the localization and expression of critical proteins integral in cell cycle regulation and DNA repair, as well as generate instability of the telomeres and promote DNA damage. Data demonstrated that OS cell growth was inhibited at 50-μM concentration, and the cells were arrested in the S phase of the cell cycle (suggesting interference with the metabolism of DNA) [54]. …”

Section: Chemopreventive Agents and Anti-cancer Compoundsmentioning

confidence: 99%

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

et al. 2017

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Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, including Notch, Wnt, Hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, and JAK/STAT, and their specific role in osteosarcoma. In addition, we highlight numerous natural compounds that have been documented to target these pathways effectively, including curcumin, diallyl trisulfide, resveratrol, apigenin, cyclopamine, and sulforaphane. We elucidate through references that these natural compounds can induce cancer signaling pathway manipulation and possibly facilitate new treatment modalities for osteosarcoma.

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“…SIRT1 deacetylates and inhibits the activities of nuclear factor κB [39], β-catenin [20], survivin [17] and c-Myc [40], which leads to suppress tumor formation and growth. The activation of SIRT1 by resveratrol inhibits proliferation and promotes apoptosis in several cancer cells [41,42]. Furthermore, studies using SIRT1 transgenic mice strongly support the hypothesis that SIRT1 is a tumor suppressor.…”

Section: Discussionmentioning

confidence: 95%

SIRT1 Is Reduced in Gastric Adenocarcinoma and Acts as a Potential Tumor Suppressor in Gastric Cancer

Zhang¹,

Cai²,

Chai³

et al. 2015

Gastrointest Tumors

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Background: Silent mating type information regulation 2 homolog 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that is involved in a variety of biological processes. Recent studies have implicated the involvement of SIRT1 in tumorigenesis, but its role remains controversial even in the same tumor type. Summary: In this study, SIRT1 expression was examined in gastric adenocarcinoma by immunohistochemistry and quantitative real-time polymerase chain reaction. Cell proliferation, cell cycle, cell apoptosis and xenograft assays were performed to elucidate the roles of SIRT1 in gastric cancer. We found that SIRT1 expression was reduced in gastric adenocarcinoma at both the protein and mRNA levels. Tissue microarray analysis revealed a positive correlation between SIRT1 and p53 expression in gastric adenocarcinoma. Inhibition of SIRT1 by EX-527 or by shRNA-mediated silencing increased cell proliferation in vitro and in vivo. SIRT1 inhibition accelerated the G1-S phase transition and reduced apoptosis by regulating key factors involved in cell cycle control and apoptosis. On the contrary, the ectopic expression of SIRT1 or the activation of SIRT1 by resveratrol was sufficient to suppress the growth of gastric cancer cells in vitro and in vivo. Key Message: In our study, the ectopic expression or activation of SIRT1 arrested cells at the G1 phase by reducing the levels of Cdk4 and cyclin D1, and induced apoptosis by increasing the ratios of Bax/Bcl-2. Practical Implications: We define SIRT1 as a potential tumor suppressor in gastric cancer. Its activation or overexpression inhibits tumor proliferation in gastric cancer by modulating cell cycle and apoptotic pathway. Strategies to activate SIRT1 could be used to treat gastric cancer.

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Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1

Cited by 50 publications

References 42 publications

WRN Loss Induces Switching of Telomerase-Independent Mechanisms of Telomere Elongation

WRN Loss Induces Switching of Telomerase-Independent Mechanisms of Telomere Elongation

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

SIRT1 Is Reduced in Gastric Adenocarcinoma and Acts as a Potential Tumor Suppressor in Gastric Cancer

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