Diosmetin enhances the sensitivity of radiotherapy by suppressing homologous recombination in endometrial cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Hu Z
PROVIDER: S-EPMC7714470 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce, and the exact role of defective DNA repair in this tumor subgroup is largely unknown. We aimed to outline the prevalence of homologous recombination repair deficiency (HRD), copy-number alterations, and somatic mutations in SEC. OncoScan SNP arrays were applied to 19 tumors in a consecutive SEC series to calculate HRD scores and explore global copy-number profiles and genomic aberrations. Copy-number signatures were established and targeted sequencing of 27 HRD-associated genes was performed. All factors were examined in relation to HRD scores to investigate potential drivers of the HRD phenotype. Ten of the 19 SEC tumors (53%) had an HRD score > 42, considered to reflect an HRD phenotype. Higher HRD score was associated with loss of heterozygosity in key HRD genes, and copy-number signatures associated with non-BRCA1/2 dependent HRD in HGSOC. A high number of SECs display an HRD phenotype. It remains to be elucidated whether this also confers PARP inhibitor sensitivity.
| S-EPMC7827019 | biostudies-literature
Project description:Radiotherapy is one of the cornerstone treatments for endometrial cancer and has successfully diminished the risk of local recurrences after surgery. However, a considerable percentage of patients suffers tumor relapse due to radioresistance mechanisms. Knowledge about the molecular determinants that confer radioresistance or radiosensitivity in endometrial cancer is still partial, as opposed to other cancers. In this review, we have highlighted different central cellular signaling pathways and processes that are known to modulate response to radiotherapy in endometrial cancer such as PI3K/AKT, MAPK and NF-κB pathways, growth factor receptor signaling, DNA damage repair mechanisms and the immune system. Moreover, we have listed different clinical trials employing targeted therapies against some of the aforementioned signaling pathways and members with radiotherapy. Finally, we have identified the latest advances in radiotherapy that have started being utilized in endometrial cancer, which include modern radiotherapy and radiogenomics. New molecular and genetic studies in association with the analysis of radiation responses in endometrial cancer will assist clinicians in taking suitable decisions for each individual patient and pave the path for personalized radiotherapy.
| S-EPMC7409033 | biostudies-literature
Project description:PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient (HRP) EOC is limited. Thus, new therapeutic strategy for HRP EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HRP cases. These data suggested that anti-angiogenic agents might potentiate the response to PARP inhibitors in EOC cells. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HRP EOC cells by suppressing HR activity. Most of the γ-H2AX foci were co-localized with RAD51 foci in control cells. However, most of the RAD51 were decreased in the bevacizumab-treated cells. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. CRY1 is one of the transcriptional coregulators associated with circadian rhythm and has recently been reported to regulate the expression of genes required for HR in cancer cells. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/VEGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC.
| S-EPMC10899666 | biostudies-literature
Project description:BackgroundHomologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer.Methods253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed.ResultsROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments.ConclusionsHigh HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.
| S-EPMC8538374 | biostudies-literature
Project description:p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. There is no study on combining APR-246 with radiation in rectal cancer; therefore, we examined whether APR-246 sensitized colorectal cancer cells with different p53 status to radiation. The combination treatment had synergistic effects on HCT116p53-R248W/-(p53Mut) cells, followed by HCT116p53+/+(p53WT) cells, and exhibited an additive effect on HCT116p53-/-(p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Comparison of the transcriptome in colorectal cancer cells with different p53 status 72hrs post-treatment with APR-246, irradiation, or the combination of APR-246 with irradiation was carried out. p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared to p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radio-sensitization effects through p53-dependent and -independent ways.
2023-05-12 | GSE232305 | GEO
Project description:ObjectiveOur study aimed to investigate the potential clinical utility of a poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (ABT-888), as a radiosensitizer in the medication of endometrial carcinoma (EC).MethodsHuman Ishikawa endometrial adenocarcinoma cells were treated with veliparib, radiotherapy (RT), or combination treatment. The viabilities, radiosensitivity enhancement ratio (sensitizer enhancement ratio (SER), and apoptosis of Ishikawa cells were, respectively, evaluated by Cell Counting Kit-8 (CCK-8), colony formation experiment, and flow cytometry. The tumor growth was assessed by xenograft mice models. Western blot assay investigated the expression of DNA damage and apoptosis-related proteins in vivo and in vitro.ResultsCell Counting Kit-8 revealed that the 10% inhibition concentration (IC10 ) and 50% inhibition concentration (IC50 ) values of veliparib-treated Ishikawa cells were 1.7 and 133.5 µM, respectively. The SER of veliparib combined with RT was 1.229 in vitro. Flow cytometry analysis results indicated that the apoptosis rate of the veliparib + RT group was markedly higher than that of the RT group in vitro (p < 0.05). Furthermore, in vivo data revealed that veliparib + RT treatment significantly decreased tumor growth compared with single treatments of veliparib or RT and with the control group (p < 0.05). Then western blot confirmed the levels of anti-phospho-histone (γH2AX), caspase-3, and B-cell lymphoma 2 (Bcl-2) associated protein X (Bax) were significantly higher in the veliparib + RT group, while the level of Bcl-2 was lower compared with that of the RT group (p < 0.05), both in vivo and in vitro.ConclusionOur results indicate that veliparib in combination with RT markedly improved the therapeutic efficiency in human endometrial carcinoma.
| S-EPMC9102625 | biostudies-literature
Project description:Homologous recombination (HR) is an important conserved process for DNA repair and ensures maintenance of genome integrity. Inappropriate HR causes gross chromosomal rearrangements and tumorigenesis in mammals. In yeast, the Srs2 helicase eliminates inappropriate recombination events, but the functional equivalent of Srs2 in higher eukaryotes has been elusive. Here, we identify C. elegans RTEL-1 as a functional analog of Srs2 and describe its vertebrate counterpart, RTEL1, which is required for genome stability and tumor avoidance. We find that rtel-1 mutant worms and RTEL1-depleted human cells share characteristic phenotypes with yeast srs2 mutants: lethality upon deletion of the sgs1/BLM homolog, hyperrecombination, and DNA damage sensitivity. In vitro, purified human RTEL1 antagonizes HR by promoting the disassembly of D loop recombination intermediates in a reaction dependent upon ATP hydrolysis. We propose that loss of HR control after deregulation of RTEL1 may be a critical event that drives genome instability and cancer.
| S-EPMC3726190 | biostudies-literature
Project description:Genetic instability, raised from dysregulation of DNA repair, is involved in tumor development. OTUB2 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding protein 2), which is responsible for DNA double-strand break (DSB), is implicated in carcinogenesis of various tumors. The effect of OTUB2 on endometrial cancer progression was then investigated. First, OTUB2 was found to be upregulated in endometrial cancer tissues and cell lines, and was closely associated with overall survival of endometrial cancer patients. Cell Counting Kit-8 and flow cytometry assay results revealed that overexpression of OTUB2 enhanced cell viability of endometrial cancer cells, while knockdown of OTUB2 inhibited cell viability. Moreover, as demonstrated by promoting cell viability and suppression of cell apoptosis, cisplatin-induced cell damage was reversed by OTUB2. Mechanistically, OTUB2 could activate Yes-associated protein/transcriptional co-activator with PDZ-binding motif (TAZ) to promote homologous recombination repair via depletion of γH2AX (phosphorylation of histone H2AX) and accumulation of Rad51. In vivo xenograft model also showed that silence of OTUB2 suppressed the growth of endometrial cancer and increased tumor sensitivity to antitumor drugs. In conclusion, OTUB2 promoted homologous recombination repair in endometrial cancer via YAP/TAZ-mediated Rad51 expression, providing a potential therapeutic target for endometrial cancer.
| S-EPMC7563931 | biostudies-literature
Project description:p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116p53-R248W/- (p53Mut) cells, followed by HCT116p53+/+ [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116p53-/- (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer.
| S-EPMC10390889 | biostudies-literature
Project description:Radiotherapy for the treatment of cancer can cause a wide range of cellular effects, the most biologically potent of which is the double-strand break in DNA. The process of repairing DNA double-strand breaks involves 1 of 2 major mechanisms: nonhomologous end joining or homologous recombination. In this review, we review the molecular mechanisms of homologous recombination, in particular as it relates to the repair of DNA damage from ionizing radiation. We also present specific situations in which homologous recombination may be dysfunctional in human cancers and how this functional abnormality can be recognized. We also discuss the therapeutic opportunities that can be exploited based on deficiencies in homologous recombination at various steps in the DNA repair pathway. Side-by-side with these potential therapeutic opportunities, we review the contemporary clinical trials in which strategies to exploit these defects in homologous recombination can be enhanced by the use of radiotherapy in conjunction with biologically targeted agents. We conclude that the field of radiation oncology has only scratched the surface of a potentially highly efficacious therapeutic strategy.
| S-EPMC4972489 | biostudies-literature