Involvement of PARP1 in prostate cancer progression

Localized prostate tumors are treated by either radical prostatectomy or radiotherapy and usually survive many years [67]. For aggressive prostate cancer, hormonal therapy is the standard treatment however; a significant amount (approximately 30%) of these tumors become hormone-independent (hormone-refractory) [11]. Prostate cancer cells that survive chemotherapy or radiation treatment may be capable to repair most radiation-induced DNA breaks. This is supported by evidence showing both in androgen dependent and independent prostate cancer cell lines in which the EGFR-ERK signaling pathway up-regulates a series of DNA repair proteins, including ERCC1, XPC, and XRCC1, in response to DNA damage [68]. These proteins efficiently repaired the damaged DNA, and enhanced the survival of cells following exposure to genotoxics [68, 69]. The activation of PARP-1 in the presence of DNA breaks consistently promotes the recruitment of XRCC1 and the physical interaction of XRCC1 with PARP-1 has been indicated as an efficient process to repair DNA breaks in a coordinated manner [39]. However, it needs to be taken into account that genetic instability may occur in those cells with unrepaired or misrepaired DNA damage. In this respect, the LNCaP prostate cancer cell line, an androgen-responsive is a good model because undergoes growth arrest, but not apoptosis after androgen deprivation, and it is also highly resistant to radiation-induced cell death [70, 71].

Given that activation of PARP-1 is absolutely dependent on DNA strand breaks [15, 26], the substantial poly(ADP-ribosyl)ation modification of PARP-1 detected during early apoptosis in LNCaP cells was consistent with the DNA damage induced by Phenoxodiol, a synthetic analogue of Genistein [72]. Although the level of PARP-1 activation and its subsequent cleavage in LNCaP cells after Phenoxodiol exposure was exhibited in a time dependent manner, the poly(ADP-ribosyl)ation automodification of PARP-1 activation during the early stages of Phenoxodiol-induced apoptosis may thus be required for progression through the death program [72]. In this respect, subsequent cleavage of PARP-1 may have prevented the depletion of NAD+ and ATP, which are needed for later steps in apoptosis [73]. However, the possibility that inhibition of the topoisomerase II activity may have caused DNA damage in cells exposed to Phenoxodiol, a well-known topoisomerase II poison, was not excluded [74]. As a matter of fact, activation of PARP-1 has also been detected in apoptotic cells exposed to different antineoplastic agents, such as adriamycin, alkylating agents, cisplatin, mitomycin C, radiation, and topoisomerase inhibitors [75].

A combined treatment of isoflavones and curcumin had a potent inhibitory effect on cellular proliferation of LNCaP cells [76]. The effects associated with this treatment were the enhanced phosphorylation of some nuclear proteins, such as ATM and Chk2 when compared to the effects of cells treated with curcumin alone. Similar effects were observed in the his-tone H2AX and p53. Interesting, curcumin also inhibited the proliferative effects of the dihy-drotestosterone (DHT), a stimulator of prostate growth [3]. The augmented levels of testosterone consistently induced activation of the DNA damage response (DDR) pathways in response to curcumin treatment by promoting the phosphorylation of CHK, H2AX and p53. This approach also induced the proteolytic cleavage of PARP-1, suggesting that activation of the DDR by polyphenols might have a suppress effect on malignant transformation, while a combined therapy of testosterone and curcumin may enhances apoptosis by promoting the release of pro-apoptotic factors, restricting thus prostate cancer progression.

To determine the signaling pathways that are induced by radiation-induced PARP-1 activation, two prostate cancer cell lines LNCaP and DU145, which express different levels of EGFR, were exposed to ionizing radiation and EGF [77]. Although the radiosensitivity was much more evident in LNCaP cells, the radiation treatment consistently reduced the clono-genic survival in both cell lines. The addition of EFG or PD184352, a MEK 1/2 inhibitor, had any significant impact on the killing of the cancer prostate cells. In contrast, PJ34, a potent inhibitor of PARP-1 [78], caused a growth arrest and markedly reduced cell death in both cell lines [77]. In support of these data, poly ADP-ribosylation of PARP-1 was also evident in LNCaP and DU145 cells after irradiation or exposure to EGF. These results are supported by findings linking EGF expression to human prostate cancer development [79, 80], the high levels of EGF secreted by LNCaP and DU145 cell lines [81, 82], as well as the enhanced invasive capacity that EGF exert on another human prostate cancer cell line (PC-3) [83]. Although the reduction of cell death was evident in cells exposed to PJ34 and EGF; however, an opposite effect was observed when PD184352 or the inhibitor of EGF receptor kinase, AG1478, alone was added to the cultures. When the same experimental approaches were applied to PARP-1-depleted cells, expression of poly ADP-ribose production was practically eliminated [78]. This study indicated that PARP-1 activation in both cell lines is linked to the EGF-ERK signaling pathway, which may be critical for the poly ADP-ribosylation and regulation of NAD+ content following irradiation, and may also be critical for cell survival after treatment for prostate cancer.

Similar apoptotic effects including, annexin-V binding and TUNEL staining, loss of mito-chondrial membrane potential the release of cytochrome c, activation of caspase-3, and increase of PARP-1 cleavage were observed in PC-3 cells treated with b-caryophyllene oxide (CPO), wortmannin, and the AKT inhibitor IV [84]. Downregulation of several proteins that are part of the PI3K/AKT/mTOR/S6K1 signaling cascade and ROS-mediate MAPKs activation were also identified, which strongly suggested that multiple cascades are involved in cell survival and proliferation of prostate cancer cells. Accordingly, LNCaP cells exposed to isochaihulactone, a lignin with proved antitumor activity in vitro and in vivo models [85], evidenced the involvement of the JNK pathway as a potential target for the activation of proteases that are crucial in the induction of caspase-3 activation and PARP-1 cleavage, hallmarks of apoptosis cell death.

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