The relationship between the expression of PARP1 and p53 in prostate cancer

It is well known that the tumor suppressor gene p53 is a key player in controlling the genetic stability in breast tumor cells [86]. More recently, it was reported that inhibition of PARP-1 by veliparib enhances DNA damage in BRCA-proficient cancer cells, a process that appears to be regulated by p53. Although a diverse response was observed in p53-mutant or -null cells, the veliparib and topotecan combination enhanced DNA damage response and cell death in these type of cells [87]. Similarly, treatment of LNCaP cells to a new ligan iso-chaihulactone, a proved inhibitor of cell proliferation and effective inducer of apoptosis in a variety of cancer cell lines, enhanced PARP-1 cleavage and increased levels of p53 in those cells that become irreversible committed to cell death [88].

Considering that PARP-1 is thought to be an important modulator of p53 [89], either by co-valent modification or by non-covalent binding of poly(ADP-ribose) on specific domains of p53, which alter its DNA binding functions [47], the binding of p53 to DNA damage promotes activation of downstream signal cascades, leading to cell cycle arrest and apoptosis. A recent report have demonstrated the efficacy of a novel CDK1, CDK2 inhibitor, dansylated VMY-1-103, in inhibiting Erb-2/Erb-3/heregulin-induced cell proliferation in LNCaP cells. Apoptosis via decreased mitochondrial membrane polarity, induction of p53 phosphoryla-tion, caspase-3 activation, and PARP-1 cleavage in these prostatic tumor cells, were also among the most relevant findings [90]. The stability of p53 as evidenced by an increase of p53 content is crucial for blocking cell cycle progression or for initiating cell death apoptosis in response to DNA damage [91, 92]. However, it cannot be excluded that other DNA repair proteins can also bind simultaneously to the damaged site and may activate alternative signaling pathways in response to genotoxic insults. The determinant of which of these mechanisms is chosen can be dependent on the magnitude of damage to the DNA.

Although p53 and PARP-1 are both damage sensor proteins and can be functionally activated by DNA damage [92, 93], evidence indicated that PARP-1 is not essential for p53 accumulation induced by DNA damage. However, PARP-1 appear to be required for the appropriate response of p53 to DNA damage [89], including its rapid and enhanced protein expression [91]. In this respect, immunoblotting analysis with antibodies against p53 were able to detect p53 protein in lysates of PARP-1 wild-type cells, but not in PARP-1 deficient cell extracts, which suggested that the reduced protein stability of p53 in cells lacking PARP-1 [94]. The functional interaction between p53 and PARP-1 in response to radiation was also reported in a human glioblastoma cell line A-17 treated with 3-aminobenzamide (3-AB), a well-known PARP-1 inhibitor. The absence of PARP-1 activity by 3-AB dramatically reduced the radiation-induced expression of the p53 downstream, the p21 gene product. In support to this observation, the gel shift analysis evidenced that 3-AB significantly inhibited the irradiation-activated p53-binding activity to its consensus sequences [95]. Similar results were observed in a (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (MPTP)-induced parkin-sonism model in which a heavy poly(ADP-ribosyla)tion modification of p53 reduced the DNA-binding activity of p53 to its consensus sequences [96].

Although the specific findings above described clearly proof that PARP-1 expression is implicated in p53 accumulation and stabilization, this effect is different to that observed in PARP-1 knock out cells exposed to N-methyl-N-nitroso urea (MNU), an alkylating agent, in which p53 is accumulated and its activation is consistently enhanced [97]. The findings in this model suggest that PARP-1 regulating p53-mediated response to genotoxic agents is probably dependent on the type of DNA damage. Accordingly the level of MDM-2 transcript, an important negative regulator of the p53, was not increased after gamma-irradiation; however, an increased in the expression of MDM-2 protein was observed in PARP-1 null cells. The increased levels of MDM-2 may provide an alternative explanation for the reduced accumulation and activation of p53 in PARP-1 null cells. Furthermore, the reduced phosphorylation of p53 may also be indicative of a defective activation of the kinases pathways in these cells [97].

Other studies have demonstrated that PARP-1 is dispensable for the repair of DNA doublestrand breaks induced by alkylating agents, UV, and gamma-radiation. In this respect, it was proposed the existence of an alternative radiation-induced pathway involving p53 that may function independently of PARP-1 involvement. Although this alternative mechanism may explain the cytotoxic response detected in PARP-1 null cells after radiation treatment [61, 98], this does not necessarily support the significant delay in the transient accumulation of p53 in PARP-1-depleted intestinal epithelial stem cells after exposure to irradiation. Similarly, the survival analysis was markedly reduced in crypts of PARP-1 knockout mice, even at radiation doses that have sublethal effects on wild type animals [65]. These observations extended the crucial role of PARP-1 to stem cells survival after DNA damage in vivo. Indeed, considering the prolonged regenerative capacity of prostate progenitor stem cells may increase their susceptibility to accumulate genetic or epigenetic alterations during their life cycle, the events may be able to increased proliferative rates, decreased cell death, and overall survival advantages over prostate progenitor stem cells, contributing thus to transformation [6, 99-104]. Along with these studies, PARP-1 inhibition may be a critical component in the treatment of some types of cancer. Additionally, other components of the cell cycle checkpoints such p53 also need to be considered in order to develop an appropriate therapy strategy to avoid relapse.

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