DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

Kurfürstová, Daniela; Bártková, Jiřina; Vrtěl, Radek; Mičková, Alena; Burdova, A.; Majera, Dušana; Mistrík, Martin; Král, Milan; Santer, Frédéric R.; Bouchal, Jan; Bártek, Jiří

doi:10.1016/j.molonc.2016.02.005

Cited by 46 publications

(50 citation statements)

References 64 publications

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“…As the DNA damage checkpoints converge on stabilization and activation of the p53 tumour suppressor protein, we next examined the p53 staining patterns in our cohort of medulloblastomas. Furthermore, to complement the assessment of biological parameters highly relevant to replication stress and oxidative DNA damage, we also examined the proliferation index (as a percentage of tumour cells positive for the Ki67 proliferation marker) and the presence and subcellular localization of the major oxidative DNA lesions, detected by an antibody to 8-oxoguanine (8-oxoG), both well-established biomarkers used also in our previous studies (Bartkova et al, 2010;Kurfurstova et al, 2016).…”

Section: Widespread Endogenous Activation Of the Atm-chk2 And Atr-chkmentioning

confidence: 99%

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

et al. 2017

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Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (cH2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress-related 53BP1 body formation, the latter in cell-non-autonomous manner. Overall, our results strongly indicate that Abbreviations 53BP1, p53-binding protein 1; ATCC, American Type Culture Collection; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia mutated and Rad3 related; Chk1, checkpoint kinase 1; Chk2, checkpoint kinase 2; COX-2, cyclooxygenase-2; DDR, DNA damage response; FBS, fetal bovine serum; FISH, fluorescence in situ hybridization; GFAP, glial fibrillary acidic protein; HCMV, human cytomegalovirus; IDH, isocitrate dehydrogenase; IE72, immediate early 72; Ini-1, integrase interactor 1; MAP-2, microtubule-associated protein 2; MDC1, mediator of DNA damage checkpoint protein 1; MOI, multiplicity of infection; NGS, next-generation sequencing; Olig2, oligodendrocyte transcription factor 2; PBS, phosphate-buffered saline; PGE2, prostaglandin E2; SHH, sonic hedgehog; WNT, wingless; γH2AX, phosphorylated histone H2AX. in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox p53 defects other than mutations may allow high proliferation despite the ongoing checkpoint signalling and that the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability ...

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Section: Widespread Endogenous Activation Of the Atm-chk2 And Atr-chkmentioning

confidence: 99%

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

et al. 2017

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“…In humans, the pervasive impact of OS has been linked to the development of a variety of diseases as diverse as Alzheimer's disease [3], cancer [4], heart failure [5] and obesity [6]. OS is also a prevalent biomarker associated with the semen of approximately 35% of infertile men [7] and the presence of elevated levels of seminal ROS has been reported arising from male reproductive tract pathologies such as varicocele [8], inflammatory [9] and prostate cancer [10]. Owing to their unique architecture, featuring an abundance of oxidizable substrates and limited intracellular antioxidant defenses, the male germ cell is particularly vulnerable to elevated levels of ROS.…”

Section: Introductionmentioning

confidence: 99%

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

2020

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A state of oxidative stress (OS) and the presence of reactive oxygen species (ROS) in the male reproductive tract are strongly correlated with infertility. While physiological levels of ROS are necessary for normal sperm functioning, elevated ROS production can overwhelm the cell’s limited antioxidant defenses leading to dysfunction and loss of fertilizing potential. Among the deleterious pleiotropic impacts arising from OS, sperm motility appears to be particularly vulnerable. Here, we present a mechanistic account for how OS contributes to altered sperm motility profiles. In our model, it is suggested that the abundant polyunsaturated fatty acids (PUFAs) residing in the sperm membrane serve to sensitize the male germ cell to ROS attack by virtue of their ability to act as substrates for lipid peroxidation (LPO) cascades. Upon initiation, LPO leads to dramatic remodeling of the composition and biophysical properties of sperm membranes and, in the case of the mitochondria, this manifests in a dissipation of membrane potential, electron leakage, increased ROS production and reduced capacity for energy production. This situation is exacerbated by the production of cytotoxic LPO byproducts such as 4-hydroxynonenal, which dysregulate molecules associated with sperm bioenergetic pathways as well as the structural and signaling components of the motility apparatus. The impact of ROS also extends to lesions in the paternal genome, as is commonly seen in the defective spermatozoa of asthenozoospermic males. Concluding, the presence of OS in the male reproductive tract is strongly and positively correlated with reduced sperm motility and fertilizing potential, thus providing a rational target for the development of new therapeutic interventions.

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“…In fact, targeting DNA repair defects with PARP1 inhibitors (PARPi) is emerging as a cancer treatment strategy, especially in BRCA1 mutation cases. However, another suitable predictive biomarker is still required, since resistance to PARPi frequently occurs (16)(17)(18). For this reason, we chose PARP1-siRNA instead of PARPi in our study.…”

Section: Discussionmentioning

confidence: 99%

PARP1-siRNA suppresses human prostate cancer cell growth and progression

et al. 2018

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Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion. Additionally, PARP1-siRNA also inhibited the proliferation of PC3 and Du145 cells. After the induction of apoptosis by docetaxel, cleaved-caspase3 of DU145 and C4-2 cells increased significantly in the PARP1-siRNA group. In the xenograft nude mouse model, PARP1-siRNA could suppress xenograft tumor size of PC3 cells and produce a more regular morphology. In vitro and in vivo, PARP1 silencing significantly downregulated vimentin expression and upregulated E-cadherin expression, both of which are epithelial-mesenchymal transition (EMT) markers. It has been revealed that PI3K inhibition could sensitize the effect of PARPi. Notably, PARP1-siRNA could suppress the expression of EGFR and p-GSK3β (Ser9) in PCa cells, which was different from PARPi. Our results indicated that PARP1-siRNA can suppress the growth and invasion capacity of PCa cells, thereby suggesting that PARP1-siRNA, which is different from PARPi, may provide a potential treatment method for PCa.

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DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

Cited by 46 publications

References 64 publications

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

PARP1-siRNA suppresses human prostate cancer cell growth and progression

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