Inhibition of proliferation and invasiveness of ovarian cancer C13* cells by a poly(ADP-ribose) polymerase inhibitor and the role of nuclear factor-κB

Abstract

Objective: To investigate the effect of the poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor PJ34 on the proliferation and invasiveness of ovarian cancer C13* cells and the role of nuclear factor-kB (NF-kB). Methods: Proliferation of C13* cells was measured using a 3 -(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide assay after incubation with PJ34 at different concentrations and for different treatment durations. In addition, expression of PARP-1 and the NF-kB p65 subunit after treatment with PJ34 was measured using Western blot and immunocytochemistry. The effect of PJ34 on cell invasiveness was examined using a transwell invasion assay. Results: PJ34 inhibited proliferation of C13* cells in a time-and dose-dependent manner. PJ34 treatment was also associated with a dose-dependent decrease in PARP-1 and NF-kB p65 expression and attenuated invasiveness of C13* cells. PARP-1 expression was positively correlated with NF-kB p65 expression. Conclusion: The PARP-1 inhibitor PJ34 can markedly inhibit the proliferation and invasiveness of C13* cells, possibly due to PARP-1-mediated attenuation of NF-kB activity.

PKC, AKT and ERK1/2-Mediated Modulations of PARP1, NF-κB and PEA15 Activities Distinctly Regulate Regional Specific Astroglial Responses Following Status Epilepticus

“…In the present study, various kinase inhibitors affected activities of PARP1, PEA15 and NF-κB in astrocytes following SE. Since PJ-34 decreases PARP1 and NF-κB expressions independent of DNA damage (Spina-Purrello et al, 2008; Wang et al, 2013), PARP1 expression is positively correlated with NF-κB expression. Indeed, PARP1 directly binds and interacts with NFκB in cellular level (Stanisavljevic et al, 2011), which are regulated by various mechanisms: PARP1 inhibitors reduce NF-κB activity by preventing the degradation of IκB (Genovese et al, 2005; Stilmann et al, 2009).…”

Targeting the NF-E2-related factor 2 pathway: A novel strategy for glioblastoma (Review)

“…Recent studies have identified several microRNAs (miRs) as post-translational targets of Nrf2 to regulate proliferation. Studies have shown that NADPH and ribose are essential for the cell proliferation in tumors (39,40), and loss of Nrf2 was found to decrease the expression of the redox-sensitive histone deacetylase HDAC4, resulting in increased expression of miR-1, miR-200a and miR-206, which markedly impaired NADPH production and ribose synthesis (41,42).…”

The Modified Phenanthridine PJ34 Unveils an Exclusive Cell-Death Mechanism in Human Cancer Cells

“…In addition, PJ34, at higher concentrations than those inhibiting PARP1, arrested the growth of human liver cancer cell lines (HepG2 and SMMC7721) [42], and the human multiple myeloma RPMI8226 cell line [43]. PJ34 acts as a potent anti-proliferating agent in human leukemia cell lines (ATLL and transformed HTLV-I) [44], and in human ovarian cancer epithelial cells (C13 cell line) [45]. The cell death-inducing efficacy of PJ34 at higher concentrations than those inhibiting PARP activity has been also reported in a variety of breast cancer cell-lines, carrying or not BRCA mutations, and in a variety of triple-negative breast cancer cell-lines [46], as well as in melanoma cell lines and melanoma metastases [47], thyroid cancer cell lines [48], HeLa cells [49] and several glioblastoma cell lines [50].…”

“…This suggested mechanism is in line with PARP inhibition sensitizing cancer cells to apoptotic cell death by DNA-damaging agents [ 53 , 58 , 59 , 60 ] and by blocking DNA double-strand break repair [ 42 ]. In view of the decreased expression of PARP1 and NFkappaB in several cancer cell types eradicated by PJ34, it has been suggested that eradication by PJ34 can be attributed to the attenuation of PARP1-dependent NF-kappaB activity that promotes proliferation [ 45 ]. However, the suggested mechanisms of PARP1-dependent activity of PJ34 in cancer cells are inconsistent with its exclusive PARP1 independent cytotoxic activity in human cancer cells at a higher concentration range than that causing PARP1 inhibition [ 29 , 30 , 31 , 35 ].…”