Inhibition of CUG-binding protein 1 and activation of caspases are critically involved in piperazine derivative BK10007S induced apoptosis in hepatocellular carcinoma cells

Abstract

Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs). Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT) assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells. Also, apoptotic bodies and terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) positive cells were observed in BK10007S treated HepG2 and SK-Hep1 cells by 4',6-diamidino-2-phenylinodole (DAPI) staining and TUNEL assay, respectively. Consistently, BK10007S increased sub G1 population in HepG2 and SK-Hep1 cells by cell cycle analysis. Furthermore, Western blotting revealed that BK10007S activated the caspase cascades (caspase 8, 9 and 3), cleaved poly (ADP-ribose) polymerase (PARP), and downregulated the expression of cyclin D1, survivin and for CUG-binding protein 1 (CUGBP1 or CELF1) in HepG2 and SK-Hep1 cells. Conversely, overexpression of CUGBP1 reduced cleavages of PARP and caspase 3, cytotoxicity and subG1 population in BK10007S treated HepG2 cells. Overall, these findings provide scientific evidences that BK10007S induces apoptosis via inhibition of CUGBP1 and activation of caspases in hepatocellular carcinomas as a potent anticancer candidate.

RNA Binding Proteins in Intestinal Epithelial Biology and Colorectal Cancer

“…CELF1 is mainly studied for its role in regulation of splicing in myotonic dystrophy [116, 117]. In the context of cancer, CELF1 can act as a tumor suppressor (in liver cancer [118]), increase caspase activity/apoptosis (in hepatocellular carcinoma [119] and esophageal cancer [120]) and act as a central node in post transcriptional regulatory programs underlying EMT (in breast cancer [121]) indicating its diverse role in carcinogenesis.…”

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

“…Remarkably, cancer-associated fibrosis is linked to modifications in the tumor microenvironment impacting cancer behavior [161]. Another compound that downregulates the expression of CELF1 is the piperazine derivative BK10007S, which induces apoptosis through this inhibition in hepatocellular carcinoma cells [162]. To our knowledge, there are no reports regarding other CELF family members.…”

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

“…In parallel, AK301 increased the expression of tumor necrosis factor (TNF) receptor 1, thereby making cancer cells more susceptible to apoptotic cell death by TNF-α [ 58 ]. Another piperazine derivate, called BK10007S, was reported to exert anti-cancer effects on HCC cell lines [ 59 ]. BK10007S (0, 3, 7 and 8.5 μM) blocked HepG2 and SK-Hep1 cell proliferation upon reduction of cyclin D1 expression.…”

“…BK10007S (0, 3, 7 and 8.5 μM) blocked HepG2 and SK-Hep1 cell proliferation upon reduction of cyclin D1 expression. Moreover, BK10007S (7 and 8.5 μM) induced apoptotic cell death by promoting caspase-3 and PARP-1 protein cleavage, and by decreasing the phosphorylation of AKT and ERK kinases and the expression of survivin and CUGBP1 proteins [ 59 ]. Collectively, such results suggest that piperazine derivates could potentially be deployed as anti-cancer agents in patients affected by CRC and HCC.…”