scholarly journals Short-term starvation synergistically enhances cytotoxicity of Niraparib via Akt/mTOR signaling pathway in ovarian cancer therapy

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Wang Zhi ◽  
Suting Li ◽  
Yuting Wan ◽  
Fuwen Wu ◽  
Li Hong
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Side Effects ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Dna Damage Repair ◽  
Ovarian Cancer Cells ◽  
Short Term ◽  
Damage Repair ◽  
Combined Use

Abstract Background Short-term starvation (STS) has gradually been confirmed as a treatment method that synergistically enhances the effect of chemotherapy on malignant tumours. In clinical applications, there are still some limitations of poly (ADP-ribose) polymerase inhibitors (PARPi), including understanding their effectiveness and side effects. Here, we sought to investigate the effect and mechanism of the combined use of STS and niraparib in the treatment of ovarian cancer. Methods In in vitro experiments, SKOV3 and A2780 ovarian cancer cells were treated with STS and niraparib alone or in combination. Cell viability was assessed with CCK-8, and cell cycle, apoptosis, DNA damage repair and autophagy were examined to explore the molecular mechanisms. Akt and mTOR inhibitors were used to examine any changes in DNA damage repair levels. Xenograft animal models were treated with STS and niraparib, and HE staining and immunohistochemistry were performed to examine the effects. Results The combined use of STS and niraparib inhibited cell proliferation and increased apoptosis more than niraparib application alone. In addition, compared with the niraparib group, the STS + niraparib group had increased G2/M arrest, DNA damage and autophagy, which indicated that STS pretreatment enhanced the cytotoxicity of niraparib. In animal experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib. In in vivo experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib and reduced the small intestinal side effects caused by niraparib chemotherapy. Conclusion STS pretreatment can synergistically enhance the cytotoxicity of niraparib. STS + niraparib is a potentially effective strategy in the maintenance therapy of ovarian cancer.

scholarly journals Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Yixuan Wang ◽  
Quan Chen ◽  
Di Wu ◽  
Qifeng Chen ◽  
Guanghui Gong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Gynecologic Cancer ◽  
Dna Damage Repair ◽  
Xenograft Model ◽  
Ovarian Cancer Cells ◽  
Lamin A ◽  
Damage Repair ◽  
Mouse Xenograft Model

AbstractOvarian cancer is the most malignant gynecologic cancer. Previous studies found that lamin-A was associated with DNA damage repair proteins but the underlying mechanism remains unclear. We speculate that this may be related to its interacting proteins, such as Hsp90. The aim of this study is to investigate the effects of Hsp90 on DNA damage repair and chemoresistance of ovarian cancer cells. In our research, co-immunoprecipitation (co-IP) and mass spectrometry (MS) were used to identify proteins interacting with lamin-A and the interaction domain. Next, the relationship between lamin-A and Hsp90 was explored by Western blotting (WB) and immunofluorescence staining. Then, effect of Hsp90 inhibition on DNA damage repair was assessed through detecting Rad50 and Ku80 by WB. Furthermore, to test the roles of 17-AAG on cell chemosensitivity, CCK-8 and colony formation assay were carried out. Meanwhile, IC50 of cells were calculated, followed by immunofluorescence to detect DNA damage. At last, the mouse xenograft model was used in determining the capacity of 17-AAG and DDP to suppress tumor growth and metastatic potential. The results showed that lamin-A could interact with Hsp90 via the domain of lamin-A1-430. Besides, the distribution of Hsp90 could be affected by lamin-A. After lamin-A knockdown, Hsp90 decreased in the cytoplasm and increased in the nucleus, suggesting that the interaction between lamin-A and Hsp90 may be related to the nucleocytoplasmic transport of Hsp90. Moreover, inhibition of Hsp90 led to an obvious decrease in the expression of DSBs (DNA double-strand break) repair proteins, as well as cell proliferation ability upon DDP treatment and IC50 of DDP, causing more serious DNA damage. In addition, the combination of 17-AAG and DDP restrained the growth of ovarian cancer efficiently in vivo and prolonged the survival time of tumor-bearing mice.

scholarly journals MTA1 promotes cell proliferation via DNA damage repair in epithelial ovarian cancer

2014 ◽  
Vol 13 (4) ◽  
pp. 10269-10278 ◽  
Author(s):  
Q.Y. Yang ◽  
J.H. Li ◽  
Q.Y. Wang ◽  
Y. Wu ◽  
J.L. Qin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Dna Damage Repair ◽  
Damage Repair

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

scholarly journals Recruitment of the Type B Histone Acetyltransferase Hat1p to Chromatin Is Linked to DNA Double-Strand Breaks

2006 ◽  
Vol 26 (9) ◽  
pp. 3649-3658 ◽  
Author(s):  
Song Qin ◽  
Mark R. Parthun
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Double Strand Break ◽  
Similar Distribution ◽  
Tail Domain ◽  
Type B ◽  
Direct Role ◽  
Damage Repair

ABSTRACT Type B histone acetyltransferases are thought to catalyze the acetylation of the NH2-terminal tails of newly synthesized histones. Although Hat1p has been implicated in cellular processes, such as telomeric silencing and DNA damage repair, the underlying molecular mechanisms by which it functions remain elusive. In an effort to understand how Hat1p is involved in the process of DNA double-strand break (DSB) repair, we examined whether Hat1p is directly recruited to sites of DNA damage. Following induction of the endonuclease HO, which generates a single DNA DSB at the MAT locus, we found that Hat1p becomes associated with chromatin near the site of DNA damage. The nuclear Hat1p-associated histone chaperone Hif1p is also recruited to an HO-induced DSB with a similar distribution. In addition, while the acetylation of all four histone H4 NH2-terminal tail domain lysine residues is increased following DSB formation, only the acetylation of H4 lysine 12, the primary target of Hat1p activity, is dependent on the presence of Hat1p. Kinetic analysis of Hat1p localization indicates that it is recruited after the phosphorylation of histone H2A S129 and concomitant with the recombinational-repair factor Rad52p. Surprisingly, Hat1p is still recruited to chromatin in strains that cannot repair an HO-induced double-strand break. These results indicate that Hat1p plays a direct role in DNA damage repair and is responsible for specific changes in histone modification that occur during the course of recombinational DNA repair.

scholarly journals Bruceine D and Afatinib Combination Inhibits Ovarian Cancer Cells Proliferation and Migration Through DNA Damage Repair and EGFR Pathway

2021 ◽  
Author(s):  
Feng Lin ◽  
Ju-fan Zhu ◽  
Luo Wang ◽  
Yuan-jun Yang ◽  
Ru-ru Zheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Dna Damage Repair ◽  
Egfr Signaling ◽  
Damage Repair ◽  
And Migration ◽  
Proliferation And Migration

Abstract Owing to the high rates of relapse and migration, ovarian cancer has been recognized as the most lethal gynecological malignancy worldwide. The activity of the EGFR signaling pathway is frequently associated with ovarian cancer cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in ovarian cancer patients failed to achieve satisfactory therapeutic effects. In this study, we identified that Bruceine D and EGFR inhibitor, afatinib, combination resulted in synergistic anti- ovarian cancer effects. The results indicated that compared with one of both drugs alone, the combination of Bruceine D and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of Bruceine D and afatinib possessed a stronger ability to inhibit the ovarian cancer cell adhesion and migration than treatment with Bruceine D or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against ovarian cancer treatment. The results support the potential of Bruceine D and afatinib combination as a therapeutic strategy for ovarian cancer patients.

scholarly journals Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xi Zhang ◽  
Guoqing Hou ◽  
Andong Liu ◽  
Hui Xu ◽  
Yang Guan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

Association of high tumor mutation (TMB) with DNA damage repair (DDR) alterations and better prognosis in ovarian cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 5512-5512 ◽  
Author(s):  
Wenjuan Tian ◽  
Boer Shan ◽  
Yuzi Zhang ◽  
Yulan Ren ◽  
Shanhui Liang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Deletions of 5q Promote Genome Instability in TP53-Mutant MDS/AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1244-1244
Author(s):  
Andreea Reilly ◽  
Stephanie Busch ◽  
Janis L. Abkowitz ◽  
Pamela S. Becker ◽  
Sergei Doulatov
Keyword(s):  
Dna Damage ◽  
Chromosomal Instability ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Dna Damage Repair ◽  
Normal Karyotype ◽  
Complex Karyotype ◽  
Differentiation Potential ◽  
Tp53 Mutations ◽  
Damage Repair

Purpose TP53 mutations in myeloid neoplasms (MDS/AML) are associated with high-risk disease, poor outcome, and complex karyotype. The molecular mechanisms which lead to global chromosomal instability remain poorly understood. Loss of 5q [del(5q)] is the most frequent cytogenetic abnormality associated with TP53 mutations suggesting that haploinsufficiency of genes on 5q contributes to chromosomal instability. Methods We reprogrammed MDS/AML patient samples to establish genetically accurate iPSC lines from preleukemic subclones. We generated iPSCs with TP53 mutations and del(5q), differentiated them to hematopoietic progenitors (HPCs), and determined the contribution of del(5q) to genome instability. Results By reprogramming MDS/AML complex karyotype patient samples, we identified iPSCs with heterozygous TP53 mutations (TP53-only), as well as iPSCs with TP53 mutations and del5(q22-q31) (TP53;del5q), and an otherwise normal karyotype. HPCs derived from TP53;del5q iPSCs had decreased multilineage differentiation potential compared to the TP53-only HPCs. Gene expression analysis of TP53;del5q HPCs revealed downregulation of genes involved in chromosome segregation and DNA damage repair. Following irradiation TP53;del5q cells had significantly delayed DNA damage repair kinetics. In order to evaluate the effects of TP53 and del(5q) on chromosomal segregation during stress, we arrested the cells in mitosis by disrupting the mitotic spindle and quantified the induction of micronuclei, a marker of chromosomal instability that occurs due to lagging chromosomes. TP53;del5q cells had an increased frequency of micronuclei formation compared to TP53-only cells. We also detected micronuclei in primary AML patient samples. Micronuclei in iPSC-HPCs and primary patient cells had disrupted nuclear envelope and DNA damage marked by y-H2AX. Conclusions Our reprogramming approach revealed that TP53 mutations are disease-initiating and frequently followed by 5q loss. We propose that del(5q) cooperates with mutant TP53 to promote genome instability via two distinct mechanisms: classical double-stranded break repair and micronuclei formation. The latter is associated with global chromosomal instability, aneuploidy, and chromothripsis. We propose that loss of 5q accelerates genome instability in TP53-mutant cells which over time impedes normal hematopoietic differentiation and leads to complex karyotype. Disclosures Becker: The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding.

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