scholarly journals The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer

2019 ◽  
Vol 20 (13) ◽  
pp. 3153 ◽  
Author(s):  
Débora Kristina Alves-Fernandes ◽  
Miriam Galvonas Jasiulionis
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Genome Stability ◽  
Sirtuin 1 ◽  
Tumor Promoter ◽  
Class Iii ◽  
Dna Damage And Repair ◽  
Skin Cancers ◽  
Primary Colon ◽  
Underlying Mechanisms

Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC), an NAD+-dependent enzyme deeply involved in gene regulation, genome stability maintenance, apoptosis, autophagy, senescence, proliferation, aging, and tumorigenesis. It also has a key role in the epigenetic regulation of tissue homeostasis and many diseases by deacetylating both histone and non-histone targets. Different studies have shown ambiguous implications of SIRT1 as both a tumor suppressor and tumor promoter. However, this contradictory role seems to be determined by the cell type and SIRT1 localization. SIRT1 upregulation has already been demonstrated in some cancer cells, such as acute myeloid leukemia (AML) and primary colon, prostate, melanoma, and non-melanoma skin cancers, while SIRT1 downregulation was described in breast cancer and hepatic cell carcinomas. Even though new functions of SIRT1 have been characterized, the underlying mechanisms that define its precise role on DNA damage and repair and their contribution to cancer development remains underexplored. Here, we discuss the recent findings on the interplay among SIRT1, oxidative stress, and DNA repair machinery and its impact on normal and cancer cells.

scholarly journals Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ding-fang Zhang ◽  
Zhi-chun Yang ◽  
Jian-qiang Chen ◽  
Xiang-xiang Jin ◽  
Yin-da Qiu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Adhesion ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Dna Damage And Repair ◽  
Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

scholarly journals Unravelling roles of error-prone DNA polymerases in shaping cancer genomes

Oncogene ◽  
2021 ◽  
Author(s):  
Cyrus Vaziri ◽  
Igor B. Rogozin ◽  
Qisheng Gu ◽  
Di Wu ◽  
Tovah A. Day
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Polymerase ◽  
Genome Stability ◽  
Dna Polymerases ◽  
The Cancer Genome Atlas ◽  
Cancer Genomes ◽  
Recent Developments ◽  
Comprehensive Picture

AbstractMutagenesis is a key hallmark and enabling characteristic of cancer cells, yet the diverse underlying mutagenic mechanisms that shape cancer genomes are not understood. This review will consider the emerging challenge of determining how DNA damage response pathways—both tolerance and repair—act upon specific forms of DNA damage to generate mutations characteristic of tumors. DNA polymerases are typically the ultimate mutagenic effectors of DNA repair pathways. Therefore, understanding the contributions of DNA polymerases is critical to develop a more comprehensive picture of mutagenic mechanisms in tumors. Selection of an appropriate DNA polymerase—whether error-free or error-prone—for a particular DNA template is critical to the maintenance of genome stability. We review different modes of DNA polymerase dysregulation including mutation, polymorphism, and over-expression of the polymerases themselves or their associated activators. Based upon recent findings connecting DNA polymerases with specific mechanisms of mutagenesis, we propose that compensation for DNA repair defects by error-prone polymerases may be a general paradigm molding the mutational landscape of cancer cells. Notably, we demonstrate that correlation of error-prone polymerase expression with mutation burden in a subset of patient tumors from The Cancer Genome Atlas can identify mechanistic hypotheses for further testing. We contrast experimental approaches from broad, genome-wide strategies to approaches with a narrower focus on a few hundred base pairs of DNA. In addition, we consider recent developments in computational annotation of patient tumor data to identify patterns of mutagenesis. Finally, we discuss the innovations and future experiments that will develop a more comprehensive portrait of mutagenic mechanisms in human tumors.

DNA Damage and Repair of Head and Neck Cancer Cells after Radio- and Chemotherapy

2009 ◽  
Vol 64 (7-8) ◽  
pp. 601-610 ◽  
Author(s):  
Pawel Rusin ◽  
Anna Walczak ◽  
Anita Zwierzchlejska ◽  
Jurek Olszewski ◽  
Alina Morawiec-Bajda ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cancer Cells ◽  
Neck Cancer ◽  
Cancer Cell Line ◽  
Repair Capacity ◽  
Dna Damage And Repair ◽  
Γ Radiation

DNA repair is critical for successful chemo- and radiotherapy of human tumours, because their genotoxic sensitivity may vary in different types of cancer cells. In this study we have compared DNA damage and the efficiency of its repair after genotoxic treatment with hydrogen peroxide, cisplatin and γ-radiation of head and neck squamous cell carcinoma (HNSCC). Lymphocytes and tissue cells from biopsies of 37 cancer patients and 35 healthy donors as well as the HTB-43 larynx cancer cell line were employed. The cell sensitivity to genotoxic treatment was estimated by the MTT survival assay. The extent of DNA damage and efficiency of its repair was examined by the alkaline comet assay. Among the examined treatments, we found that HNSCC cells were the most sensitive to γ-radiation and displayed impaired DNA repair. In particular, DNA damage was repaired less effectively in cells from HNSCC metastasis than healthy controls. In conclusion, our results suggest that the different genotoxic sensitivity of HNSCC cells may depend on their DNA repair capacity what in turn may be connected with the effectiveness of head and neck cancer therapy.

scholarly journals The Australian fruit Illawarra plum (Podocarpus elatusEndl., Podocarpaceae) inhibits telomerase, increases histone deacetylase activity and decreases proliferation of colon cancer cells

2012 ◽  
Vol 109 (12) ◽  
pp. 2117-2125 ◽  
Author(s):  
Erin L. Symonds ◽  
Izabela Konczak ◽  
Michael Fenech
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Class Iii ◽  
Ht 29

Fruit antioxidants have many health benefits including prevention of cancer development. The native Australian bush fruit Illawarra plum (Podocarpus elatusEndl., Podocarpaceae) has a high content of anthocyanin-rich phenolics, with an antioxidant capacity at levels higher than most fruits. In the present study the molecular mechanisms of the anti-proliferative activity of Illawarra plum on colorectal cancer cells were investigated. Non-tumorigenic young adult mouse colonic (YAMC) cells and tumorigenic human colonic (HT-29) cells were treated with a polyphenolic-rich Illawarra plum extract (0–1000 μg/ml). Illawarra plum had anti-proliferative properties in only the cancer cells, with growth suppressed in a dose- and time-dependent manner. Treatment of HT-29 cells with Illawarra plum extract (500 μg/ml; 24 h) was also associated with a 2-fold increase in apoptosis, and a cell cycle delay in the S phase (P< 0·01). Assessment of biomarkers for DNA damage revealed that plum treatment caused a 93 % down-regulation of telomerase activity (P< 0·001) and a decrease in telomere length (up to 75 %;P< 0·01). Treatment with Illawarra plum extract also induced morphological alterations to HT-29 cells that were suggestive of induction of autophagy, as the formation of cytoplasmic vacuoles was observed in many cells. This could be induced by the increased (6-fold) histone deacetylase (HDAC) activity (P< 0·001) and the trend for increased expression of the class III HDAC sirtuin 1. The present study has shown that Illawarra plum extract is able to reduce the proliferation of colon cancer cells by altering the cell cycle, increasing apoptosis and possibly inducing autophagy. The active ingredients in Illawarra plum may provide an alternative chemoprevention strategy to conventional chemotherapy.

scholarly journals Cytotoxic and Radiosensitising Effects of a Novel Thioredoxin Reductase Inhibitor in Brain Cancers

2021 ◽  
Author(s):  
Anqi Yao ◽  
Sarah J. Storr ◽  
Martyn Inman ◽  
Lucy Barwell ◽  
Christopher J. Moody ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Brain Cancer ◽  
Oxidative Dna Damage ◽  
Epithelial Mesenchymal Transition ◽  
Single Agent ◽  
Thioredoxin Reductase ◽  
Mesenchymal Transition ◽  
Hypoxic Conditions ◽  
Underlying Mechanisms

Abstract The thioredoxin (Trx) system, a key antioxidant pathway, represents an attractive target for cancer therapy. This study investigated the chemotherapeutic and radiosensitising effects of a novel Trx reductase (TrxR) inhibitor, IQ10, on brain cancer cells and the underlying mechanisms. Five brain cancer cell lines and a normal cell type were used. TrxR activity and expression were assessed by insulin reduction assay and Western blotting respectively. IQ10 cytotoxicity was evaluated using growth curve, resazurin reduction and clonogenic assays. Radiosensitivity was examined using clonogenic assay. Reactive oxygen species levels were examined by flow cytometry and DNA damage assessed by immunofluorescence. Epithelial-mesenchymal transition (EMT) related genes expression was examined by RT-PCR array. IQ10 significantly inhibited TrxR activity but did not affect the Trx system protein expression in brain cancer cells. The drug exhibited potent anti-proliferative and cytotoxic effects against brain cancer cells under both normoxic and hypoxic conditions in both 2D and 3D systems, with IC50s in the low micromolar range. It was up to ~1000 fold more potent than temozolomide. IQ10 substantially sensitised various brain cancer cells to radiation, with such effect being due, in part, to functional inhibition of TrxR, making cells less able to deal with oxidative stress, and leading to increased oxidative DNA damage. IQ10 significantly downregulated EMT associated gene expression suggesting potential antiinvasive and antimetastatic properties. This study suggests that IQ10 is a potent anticancer agent, and could be used as either a single agent or combined with radiation, to treat brain cancers.

scholarly journals SIRT7: a sentinel of genome stability

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210047
Author(s):  
Ming Tang ◽  
Huangqi Tang ◽  
Bo Tu ◽  
Wei-Guo Zhu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Biological Function ◽  
Critical Role ◽  
Class Iii ◽  
Cellular Processes ◽  
The Past ◽  
Damage Response ◽  
Normal Gene

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

Design of a phase 0 microdosing trial for correlation of platinum-induced DNA damage to chemotherapy outcomes

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
C. Pan ◽  
T. Li ◽  
M. He ◽  
R. de Vere White ◽  
D. Gandara ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Therapeutic Dose ◽  
Transitional Cell ◽  
Drug Uptake ◽  
Therapeutic Drug ◽  
Dna Damage And Repair ◽  
Tumor Xenografts ◽  
Response To Chemotherapy ◽  
Phase 0

2543 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS), an ultrasensitive method for measuring radiocarbon, can detect [14C]carboplatin bound to the DNA of cancer cells from cell culture, mice bearing tumor xenografts and patients receiving subtoxic microdoses of compound. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Relevant parameters such as drug influx/efflux, intracellular drug inactivation, DNA damage and repair, were measured and correlated with response to chemotherapy. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung or bladder transitional cell cancers who are planning to receive Pt-based chemotherapy. One microdose of [14C]carboplatin is administered to these patients 4 hours before biopsy. Pt-induced DNA damage and repair in tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Results: Preclinical studies showed that AMS can detect Pt-DNA damage when cancer cells and mice with tumor xenografts are exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage are directly proportional to the damage caused by a therapeutic drug dose (p<0.001); and these levels of DNA damage correlate with chemoresistance as measured by MTT assay. Measuring drug uptake/efflux and intracellular inactivation allows insights into resistance mechanisms. These data support the conclusion that the levels of DNA damage induced by microdosing can potentially predict chemoresistance in patients. Consequently, a Phase 0 microdosing trial is in progress. Conclusions: These results support a phase 0 microdosing trial employing AMS to identify chemoresistance and determine the underlying chemoresistant mechanisms for personalized therapy before patients receive cytotoxic chemotherapy. [Table: see text]

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