An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme-Role in Pathogenesis and Therapeutic Perspective.

Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified. Using an animal model, it was shown that autophagy is required for GBM development. Temozolomide (TMZ) is the key drug in GBM chemotherapy and it was reported to induce senescence, autophagy and apoptosis in GBM. In some GBM cells, TMZ induces small toxicity despite its significant concentration and GBM cells can be intrinsically resistant to apoptosis. Resveratrol, a natural compound, was shown to potentiate anticancer effect of TMZ in GBM cells through the abrogation G2-arrest and mitotic catastrophe resulting in senescence of GBM cells. Autophagy is the key player in TMZ resistance in GBM. TMZ can induce apoptosis due to selective inhibition of autophagy, in which autophagic vehicles accumulate as their fusion with lysosomes is blocked. Modulation of autophagic action of TMZ with autophagy inhibitors can result in opposite outcomes, depending on the step targeted in autophagic flux. Studies on relationships between senescence, autophagy and apoptosis can open new therapeutic perspectives in GBM.

Regulation of DNA Damage Response and Homologous Recombination Repair by microRNA in Human Cells Exposed to Ionizing Radiation.

Ionizing radiation may be of both artificial and natural origin and causes cellular damage in living organisms. Radioactive isotopes have been used significantly in cancer therapy for many years. The formation of DNA double-strand breaks (DSBs) is the most dangerous effect of ionizing radiation on the cellular level. After irradiation, cells activate a DNA damage response, the molecular path that determines the fate of the cell. As an important element of this, homologous recombination repair is a crucial pathway for the error-free repair of DNA lesions. All components of DNA damage response are regulated by specific microRNAs. MicroRNAs are single-stranded short noncoding RNAs of 20-25 nt in length. They are directly involved in the regulation of gene expression by repressing translation or by cleaving target mRNA. In the present review, we analyze the biological mechanisms by which miRNAs regulate cell response to ionizing radiation-induced double-stranded breaks with an emphasis on DNA repair by homologous recombination, and its main component, the RAD51 recombinase. On the other hand, we discuss the ability of DNA damage response proteins to launch particular miRNA expression and modulate the course of this process. A full understanding of cell response processes to radiation-induced DNA damage will allow us to develop new and more effective methods of ionizing radiation therapy for cancers, and may help to develop methods for preventing the harmful effects of ionizing radiation on healthy organisms.

Mitochondrial DNA copy number, damage, repair and degradation in depressive disorder.

Objectives: We aimed to explore mitochondrial DNA (mtDNA) copy number, damage, repair and degradation in peripheral blood mononuclear cells (PBMCs) of patients with depression and to compare the results with healthy subjects.Methods: Total genomic DNA was isolated from PBMCs of 25 depressed and 60 healthy subjects before, immediately after, and 3 h after the exposure to H2O2. Evaluation of mtDNA copy number was performed using real-time PCR and 2-ΔCt methods. Semi-long run real-time PCR was used to estimate the number of mtDNA lesions.Results: Baseline mtDNA copy number did not differ in cells of healthy and depressed subjects; however, it was negatively correlated with the severity of the episode. After a 10-min challenge with hydrogen peroxide (H2O2), depressed patients' PBMCs exhibited slower changes of the copy number, indicating a lower efficiency of mtDNA degradation compared to controls. Moreover, a significantly higher number of mtDNA lesions was found in depressed patients at the baseline as well as at other experimental time points. mtDNA lesions were also elevated in depressed patient cells immediately after H2O2 exposure. Induction of oxidative stress had no significant influence on the cells of controls.Conclusions: We are the first to show that impairment in repair and degradation of mtDNA may be involved in the pathophysiology of depression.

Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.