p53 Mutant Human Glioma Cells Are Sensitive to UV-C-Induced Apoptosis Due to Impaired Cyclobutane Pyrimidine Dimer Removal

Abstract

The p53 protein is a key regulator of cell responses to DNA damage, and it has been shown that it sensitizes glioma cells to the alkylating agent temozolomide by up-regulating the extrinsic apoptotic pathway, whereas it increases the resistance to chloroethylating agents, such as ACNU and BCNU, probably by enhancing the efficiency of DNA repair. However, because these agents induce a wide variety of distinct DNA lesions, the direct importance of DNA repair is hard to access. Here, it is shown that the induction of photoproducts by UV light (UV-C) significantly induces apoptosis in a p53-mutated glioma background. This is caused by a reduced level of photoproduct repair, resulting in the persistence of DNA lesions in p53-mutated glioma cells. UV-C-induced apoptosis in p53 mutant glioma cells is preceded by strong transcription and replication inhibition due to blockage by unrepaired photolesions. Moreover, the results indicate that UV-C-induced apoptosis of p53 mutant glioma cells is executed through the intrinsic apoptotic pathway, with Bcl-2 degradation and sustained Bax and Bak up-regulation. Collectively, the data indicate that unrepaired DNA lesions induce apoptosis in p53 mutant gliomas despite the resistance of these gliomas to temozolomide, suggesting that efficiency of treatment of p53 mutant gliomas might be higher with agents that induce the formation of DNA lesions whose global genomic repair is dependent on p53.

Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells

“…The reason for this effect is that the number of cells in G 1 and G 2/ M (i.e., cells undergoing death) is lower with a lower value for IC50 s . This result suggests that arrest in S phase could act as a shield against cell death and thus contributes to drug resistance, and is consistent with reports linking increased chemotherapy resistance with increased efficiency of cell cycle arrest [17-19]. Increasing the value of k d results in a shift from a linear increase in the number of dead cells with time (Fig.…”

Autophagy and genomic integrity

“…4,17 The kinases ATM and ATR have key roles sensing DNA breaks and activating downstream components of DDR, such as Chk1, Chk2 and p53. 72,73 p53 is an important protein in DDR, inducing the transcription of key genes involved in cell cycle arrest, DNA repair, apoptosis 74,75 and, more recently described, in autophagy. 76 Two central components, p53 and mTOR, link DDR to autophagy ( Figure 3 and Table 1).…”

“…As summarized in Table 2, the majority of studies showed that inhibition of autophagy in cells treated with DNA damaging agents leads to increased cell death, supporting a protective Regulates cell cycle arrest, DNA repair and apoptosis in response to DNA damage. 74,75,77 Induces autophagy in response to DNA damage through transcription of ULK1, ULK2, DRAM, Sestrins 1/2 and ISG20L1. 13,14,78,88 In the cytoplasm, inhibits autophagy through AMPK inhibition.…”

“…In this scenario, transcription factors such as p53, p73 and E2F1 would have pivotal roles, as they were not only shown to promote DNA repair, cell cycle arrest or apoptosis in response to different degrees of DNA damage, but also to control autophagy. 74,75,91,93 Thus, we hypothesize that after low doses of DNA damage, autophagy activation by these transcription factors would result in clearance of membrane-permeabilized mitochondria, 94 generation of dNTPs and/or ATP for DNA repair activity, 47,48 degradation of pro-apoptotic proteins such as active caspase 8 95 and elimination of p62, thus preventing p38-hyperactivation. 96 Supporting the role of p53 in autophagy and cell survival, p53 mediates the transcription of parkin, 97 suggesting that p53 could regulate transcription of mitophagy genes in response to genomic damage, thus counterbalancing mitochondrial apoptotic signaling.…”

Bactericidal effects of 310 nm ultraviolet light-emitting diode irradiation on oral bacteria

“…The peak of DNA absorption of UV light is 260 nm and its wavelength impairs bacterial DNA by forming pyrimidine (6–4) pyrimidone photoproducts and cyclobutane pyrimidine dimers. The DNA damage also leads to the repression of its transcription and replication and finally induces to cell death [12, 15–17]. UVB light has the same effects to DNA [12, 15], however, there have been few studies on the bactericidal effect of UVB light, especially the effect on oral bacteria.…”