A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Shah, Ashish; Patel, Chhagan N.; Sanghavi, Kirtan P

doi:10.1515/folmed-2017-0067

Cited by 14 publications

(8 citation statements)

References 39 publications

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“…Our results suggest that IL-12p35 KO promotes mitochondrial AIF translocation to the nucleus. In contrast to AIF, PARP is mainly a DNA repair enzyme existing in the nucleus, and activated PARP can prevent DNA damage and inhibit apoptosis [28]. In a recent study, expression of activated PARP was also observed to increase in aging brain tissue, which was consistent with our results and closely related to both DNA damage and apoptosis of brain cells [29].…”

Section: (B) the Mitosox Red Mitochondrial Superoxidesupporting

confidence: 91%

Interleukin-12p35 deficiency enhances mitochondrial dysfunction and aggravates cardiac remodeling in aging mice

Wang

et al. 2020

Aging

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Our previous studies have demonstrated that interleukin-12p35 knockout (IL-12p35 KO) regulates the progression of various cardiovascular diseases, such as acute cardiac injury and hypertension. The aims of this study were to investigate whether IL-12p35 KO affects aging-related cardiac remodeling and to explore the possible mechanisms. First, the effects of IL-12p35 KO on heart structure and function were detected, and the results showed that IL-12p35 KO exacerbated cardiac remodeling and increased cardiac senescence-related protein levels in aged mice. In addition, whether IL-12p35 KO regulates cardiac senescence-related protein expression, cardiac mitochondrial dysfunction and cardiomyocyte apoptosis was also investigated. IL-12p35 KO increased mitochondrial calcium fluorescence intensity and ROS fluorescence intensity, while it reduced mitochondrial membrane potential. Furthermore, reduced mitochondrial complex (I-IV) activity and ATP levels and increased apoptosis-inducing factor (AIF)-related cardiomyocyte apoptosis were observed in aged IL-12p35 KO mice compared with wild-type mice. Our results demonstrate that aging is aggravated by IL-12p35 KO and that the mechanism may be related to exacerbation of mitochondrial dysfunction and AIF-related cardiomyocyte apoptosis.

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Section: (B) the Mitosox Red Mitochondrial Superoxidesupporting

confidence: 91%

Interleukin-12p35 deficiency enhances mitochondrial dysfunction and aggravates cardiac remodeling in aging mice

Wang

et al. 2020

Aging

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“…However, whether PARPi has potential effects in addition to BRCA1/BRCA2 mutation carriers remains an important question. Evidence has suggested that MYC expression can be used to stratify TNBC patients for therapy with PARPi independent of BRCA status because MYC is a transcriptional regulator of RAD51 [17] The recruitment of the repair protein RAD51 by BRCA2 and BRCA1 to the damaged DNA sites is an important step in HR repair following DNA damage [24]. Recently, a study in ovarian cancer also suggested that BRCA1/2 mRNA levels may be reliable biomarkers to predict responsiveness to PARPi [25].…”

Section: Discussionmentioning

confidence: 99%

SPAG5 upregulation contributes to enhanced c-MYC transcriptional activity via interaction with c-MYC binding protein in triple-negative breast cancer

Zhou

et al. 2019

J Hematol Oncol

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BackgroundTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks effective therapeutic targets. Sperm-associated antigen 5 (SPAG5) is a mitotic spindle-associated protein that is involved in various biological processes in cervical cancer and bladder urothelial carcinoma. However, the role of SPAG5 in TNBC remains undefined.MethodsThe expression of SPAG5 was examined in TNBC patients via quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC). The biological functions of SPAG5 in TNBC and the underlying mechanisms were investigated in vitro and in vivo.ResultsSPAG5 expression was significantly upregulated in TNBC tissues compared with that in paired adjacent noncancerous tissues (ANTs). High SPAG5 expression was associated with increased lymph node metastasis and high risk of local recurrence. SPAG5 protein expression was significantly associated with poor disease-free survival in TNBC. Gene set enrichment analysis of TNBC data from The Cancer Genome Atlas (TCGA) indicated that high SPAG5 expression was significantly associated with cell cycle and the ATR-BRCA pathway. Functional assays demonstrated that SPAG5 expression promoted tumor growth in vitro and in vivo. In addition, SPAG5-silenced cells were more sensitive to the PARP inhibitor (PARPi) olaparib. Mechanistically, SPAG5 interacted with c-MYC binding protein (MYCBP), thereby increasing MYCBP protein levels and leading to increased c-MYC transcriptional activity, which promoted the expression of the c-MYC target genes: CDC20, CDC25C, BRCA1, BRCA2, and RAD51.Knockdown of MYCBP or c-MYC abolished the SPAG5-induced cell-cycle progression and cell proliferation of TNBC.ConclusionsCollectively, our results indict that SPAG5 is an efficient prognostic factor in TNBC, and that SPAG5 knockdown increases the sensitivity of TNBC to the PARPi olaparib. SPAG5 promotes tumor growth and DNA repair by increasing c-MYC transcriptional activity via interaction with MYCBP. The SPAG5/MYCBP/c-MYC axis may represent a potential therapeutic target for TNBC treatment.Electronic supplementary materialThe online version of this article (10.1186/s13045-019-0700-2) contains supplementary material, which is available to authorized users.

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“… 17 , 18 For example, G2M_checkpoint participated in regulating cells growth and apoptosis of ovarian tumor, 19 colon cancer, 20 hepatocellular carcinoma, 21 and breast cancer. 22 Similarly, E2F_targets, 23 – 25 DNA-repair 26 – 28 and MYC_targets_V2 29 – 31 pathways were found to participate in tumor therapy, drug resistance, immune evasion and progression. These results further supported that GINS2 participated in the initiation and progression of lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

<p>GINS2 Functions as a Key Gene in Lung Adenocarcinoma by WGCNA Co-Expression Network Analysis</p>

Tian¹,

Yang²,

He³

et al. 2020

OTT

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Background Lung adenocarcinoma is one of the malignant tumors in the world. This study aimed to explore the biological mechanism of GINS2 in lung adenocarcinoma. Materials and Methods Raw data were downloaded from GEO. WGCNA co-expression network and PPI network were established to identify the hub gene. The expression profile and clinical features of GINS2 were collected from TCGA-LUAD cohort. Survival analysis in TCGA-LUAD cohort was plotted by R package. GSEA was analyzed via GSEA software. MTS, Transwell and apoptosis assays were used to detect the proliferation, migration and apoptotic abilities of lung adenocarcinoma cells. Results GINS2 was identified as the hub gene via WGCNA co-expression network and PPI network. Higher GINS2 expressions were observed in TCGA-LUAD cohort, GSE32863 and clinical samples dataset. Overexpression of GINS2 had a significantly negative connection with poor survival outcome. GSEA results revealed that GINS2 could be enriched in “HALLMARK_G2M_CHECKPOINT”, “HALLMARK_E2F_TARGETS”, “HALLMARK_DNA_REPAIR” and “HALLMARK_MYC_TARGETS_V2”. Overexpression of GINS2 promoted tumor cell proliferation and migration and suppressed cell apoptosis. Conclusion Our results explored that GINS2 functioned as an oncogene in lung adenocarcinoma, and suggested that GINS2 could act as a promising prognosis biomarker for lung adenocarcinoma.

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Cited by 14 publications

References 39 publications

Interleukin-12p35 deficiency enhances mitochondrial dysfunction and aggravates cardiac remodeling in aging mice

Interleukin-12p35 deficiency enhances mitochondrial dysfunction and aggravates cardiac remodeling in aging mice

SPAG5 upregulation contributes to enhanced c-MYC transcriptional activity via interaction with c-MYC binding protein in triple-negative breast cancer

<p>GINS2 Functions as a Key Gene in Lung Adenocarcinoma by WGCNA Co-Expression Network Analysis</p>

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