Poly(ADP-Ribose) Polymerase Inhibition Down-Regulates Expression of Metastasis-Related Genes in CT26 Colon Carcinoma Cells

Abstract

Objectives: The current study was designed to test the hypothesis that inhibition of poly(ADP-ribose) polymerase in colorectal cancer mediates down-regulation of metastasis-related gene expression through the regulation of nuclear factor-κB (NF-κB) activity. Methods: Mouse colon carcinoma cells (CT26) were treated with and without the PARP inhibitor 5-aminoisoquinolin-1(2H)-one hydrochloride (5-AIQ). We investigated adhesion, migration and invasion of differently treated CT26 cells. In addition, the expression levels of PARP, NF-κB, integrin β₁, MMP-9 and MMP-2 as well as the activities of NF-κB, MMP-9 and MMP-2 were determined by Western blot, electrophoretic mobility gel shift assay and zymography, respectively. Results: Inhibition ofPARP attenuated the adhesion of CT26 cells to the extracellular matrix and their migration and invasion through Matrigel. In addition, the results of Western blot showed that the expression levels of PARP, NF-κB, integrin β₁, MMP-9 and MMP-2 were reduced in 5-AIQ-treated CT26 cells; the activities of NF-κB, MMP-9 and MMP-2 were also suppressed. Conclusions: Inhibition of PARP down-regulates the expression of metastasis-related genes in mouse colon carcinoma cells. This could be, at least in part, through the regulation of NF-κB activity, but the precise mechanisms of action remain to be elucidated.

RNA Interference of PARG Could Inhibit the Metastatic Potency of Colon Carcinoma Cells via PI3-Kinase/Akt Pathway

“…3c, d). This demonstrates diminished activation of NF-κB in PARG-shRNA cells resulting in decreased expression of its dependent genes [35][36][37][38] Silencing PARG Inhibits Metastasis of Colon Carcinoma MMP2 and MMP9 (Fig. 4c, d).…”

PARP and PARG Inhibitors—New Therapeutic Targets in Cancer Treatment

“…ABT-888 also potentiated radiation in HCT-116 colon carcinoma model [99] while, potent non-toxic PARP inhibitors used in LoVo human colon carcinoma cells showed excellent chemopotentiation for relevant anti tumor therapies [100]. Another PARP inhibitor, 5-Aminoisoquinolinone (5-AIQ) was found to prevent adhesion of HT-29 colonic cells to HUVEC [101] and in CT26 mouse adenocarcinoma cells it inhibited proliferation, migration of tumor cells, downregulated NF-K B as well as its expression genes in metastasis such as integrinβ1, MMP-2 and MMP-9 thus, putting forward its use in clinical trials [102]. Gallotannin (PARG inhibitor) used in CT26 colon carcinoma cell lines was found to suppress tumor growth factors [75].…”

5-Aminoisoquinolinone Reduces the Expression of Vascular Endothelial Growth Factor-C via the Nuclear Factor-kappa B Signaling Pathway in CT26 Cells

“…Our previous studies had also showed that PARP-1 inhibition can dramatically decrease the activation of nuclear factor-kB and its DNA-binding activity (Li et al, 2009, Li et al, 2012. PARP-1 has been reported to be a co-activator of NF-kB in many inflammatory disorders (Pétrilli et al, 2004;Zheng et al, 2004).…”