The Therapeutic Role of PNU-74654 in Hepatocellular Carcinoma May Involve Suppression of NF-κB Signaling

Abstract

Background and Objectives: PNU-74654, a Wnt/β-catenin inhibitor, has reported antitumor activities; however, the therapeutic potential of PNU-74654 in hepatocellular carcinoma (HCC) has not been investigated in detail. The aim of this study was to clarify the cytotoxic effects of PNU-74654 against HCC and to uncover its molecular mechanism. Materials and Methods: HepG2 and Huh7 liver cancer cell lines were selected to determine the antitumor properties of PNU-74654. Survival of the liver cancer cells in response to PNU-74654 was assessed by cell viability assays, and the apoptosis effect of PNU-74654 was analyzed by flow cytometry and visualized by Hoechst staining. An oncology array was used to explore the underlying molecular routes of PNU-74654 action in the cells. The migration properties were examined with a wound healing assay, and western blotting was conducted to evaluate protein expression. Results: Treatment with PNU-74654 decreased cell viability and inhibited cell migration. The cell cycle analysis and Hoechst staining revealed an increase in the population of cells at the sub-G1 stage and apoptotic morphological changes in the nucleus. The oncology array identified 84 oncology-related proteins and a suppressed expression of Bcl-xL and survivin. Western blotting showed that PNU-74654 could interfere with cell cycle-related proteins through the NF-κB pathway. Conclusions: PNU-74654 shows antiproliferative and antimigration effects against HepG2 and Huh7 cells, and its antitumor activity may be attributable to its interference in cell cycle regulation and the NF-κB pathway.

PNU-74654 Induces Cell Cycle Arrest and Inhibits EMT Progression in Pancreatic Cancer

“…Furthermore, tumor growth was inhibited by the combined use of PNU-74654 and 5-FU by altering the expression of reactive oxygen species, superoxide dismutase, MCP-1, p53, and TNF-α. In hepatocellular carcinoma, the PNU-74654 treatment of HepG2 and Huh7 cells suppressed NF-κB pathway activity, thereby interfering with the cell cycle and promoting antiproliferative and antimigration effects [ 25 ]. In adrenocortical cancer, PNU-74654 treatment prevented the binding of TCF to β-catenin and decreased CTNNB1 mRNA expression and nuclear β-catenin accumulation, thereby promoting apoptosis cells, reducing cell viability, and impairing adrenal steroid secretion [ 21 ].…”

“…The same synergistic effect was also observed for colorectal cancer, as the combination of PNU-74654 plus 5-FU increased the levels of reactive oxygen species in CT-26 cells, thereby promoting the sensitivity of cancer cells to chemotherapy drugs [ 24 ]. The antiproliferative and antimigration effects of PNU-74654 against hepatocellular carcinoma have also been demonstrated, as this inhibitor suppressed the nuclear factor κB (NF-κB) pathway and disrupted the cell cycle of cancer cells [ 25 ]. However, despite many preclinical studies, the mechanism underlying the anticancer effects of PNU-74654 in PC is not yet clear.…”

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…NF-κB is another pathway in HCC tumorigenesis and its upregulation by PIGU promotes tumorigenesis in HCC [140] . Suppression of NF-κB renders cell cycle arrest in HCC cells [141] and NF-κB down-regulation is responsible for PNU-74,654′s therapeutic indexes [142] . During the preparation of liposomes by reverse-phase evaporation, beta-Sitosterol is used to mediate liver-targeting feature in HCC cells and NF-κB-siRNA has been loaded in cationic liposomes to protect it against degradation and suppress carcinogenesis [143] .…”