Systemic dna damage: Mechanisms, effects and mitigation strategies

Georgakilas, Alexandros G.; Gorgoulis, Vassilis G.

doi:10.1016/j.semcancer.2016.04.001

Cited by 2 publications

(1 citation statement)

References 11 publications

(12 reference statements)

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“…According to our model, treatment of androgen-sensitive cells with AR inhibitors leads to CDC6 downregulation; this, however, may be responsible for DNA under-replication, potentially leading to DNA damage as cells may enter mitosis with incompletely replicated DNA or unresolved chromosomes [ 67 , 68 ]. DNA under-replication becomes permissive for gradual accumulation of genomic instability, which eventually inactivates tumor suppressive mechanisms as a result of selective pressure [ 19 , 21 , 22 , 25 , 69 ]. The GATA2-CDC6 axis, which functions as such a tumor suppressive mechanism in an androgen-sensitive environment may, therefore, be rewired to contribute to oncogenic progression.…”

Section: Discussionmentioning

confidence: 99%

A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

Mourkioti

Polyzou

Veroutis

et al. 2023

J Exp Clin Cancer Res

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Background Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed. Methods Androgen-dependent (LNCaP) and –independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy. Results We demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression. Conclusions We identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.

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Section: Discussionmentioning

confidence: 99%

A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

Mourkioti

Polyzou

Veroutis

et al. 2023

J Exp Clin Cancer Res

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Individual Radiation Sensitivity and Biomarkers: Molecular Radiation Biology

Ainsbury,

Abrantes,

Baatout

et al. 2023

Radiobiology Textbook

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In recent years, scientific understanding of the changes radiation makes to the various tissues of the body has vastly increased. Identification of biological markers of radiation exposure and response has become a wide field with an increasing interest across the radiation research community. This chapter introduces the concepts of individual radiosensitivity, radiosusceptibility, and radiodegeneration, which are the key factors to classify radiation responses. Biomarkers are then introduced, and their key characteristics as well as classification are explained, with a particular focus on those biomarkers which have been identified for use in epidemiological studies of radiation risk—as this is a crucial topic of current interest within radiation protection. Brief information on collection of samples is followed by a detailed presentation of predictive assays in use in different settings including clinical applications with responses assessed chiefly in tissue biopsy or blood samples. The sections toward the end of this chapter then discuss the evidence associated with the relationship between age and separately sex, and radiosensitivity, as well as some genetic syndromes associated with radiosensitivity. The final section of this chapter provides a brief summary of how our current knowledge can further support individual, personalized, uses of radiation, particularly in clinical settings.

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Systemic dna damage: Mechanisms, effects and mitigation strategies

Cited by 2 publications

References 11 publications

A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer

Individual Radiation Sensitivity and Biomarkers: Molecular Radiation Biology

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