Antiproliferative and toxicogenomic effects of resveratrol in bladder cancer cells with different TP53 status

Abstract

The antitumor activity of resveratrol, a polyphenolic compound found mainly in grapes, has been studied in several types of cancer. In bladder cancer, its antiproliferative effects have already been demonstrated; however, its mechanism of action is not completely understood. The aim of this study was to evaluate resveratrol antitumor activity (12.5, 25, 50, 100, 150, 200, and 250 μM) and its possible mechanisms of action in bladder tumor cells with different TP53 gene status (RT4, grade 1, TP53 wild type; 5637‐grade 2 and T24‐grade 3, TP53 mutated). Cell proliferation, clonogenic survival, morphological changes, cell cycle progression, apoptosis rates, genotoxicity, global methylation, immunocytochemistry for p53 and PCNA and relative expression profiles of the AKT, mTOR, RASSF1A, HOXB3, SRC, PLK1, and DNMT1 were evaluated. Resveratrol decreased cell proliferation and induced DNA damage in all cell lines. Regarding the long‐term effects, resveratrol reduced the number of colonies in all cell lines; however, TP53 wild type cells were more resistant. Increased rates of apoptosis were found in the TP53 wild type cells and this was accompanied by AKT, mTOR, and SRC downregulation. In addition, the resveratrol antiproliferative effects in wild type TP53 cells were accompanied by modulation of the DNMT1 gene. In the TP53 mutated cells, cell cycle arrest at S phase with PLK1 downregulation was observed. Additionally, there was modulation of the HOXB3/RASSF1A pathway and nuclear PCNA reduction in the highest‐grade cells. In conclusion, resveratrol has antiproliferative activity in bladder tumor cells; however, the mechanisms of action are dependent on TP53 status. Environ. Mol. Mutagen., 60:740–751, 2019. © 2019 Wiley Periodicals, Inc.

MicroRNA-340 Inhibits Bladder Cancer Cell Growth by Downregulating Glucose Transporter-1

“…Proliferating cell nuclear antigen (PCNA), is one of important proteins, involving many cellular processes, such as DNA replication, transcription and cell cycle progression. 15,16 In the present work, the mRNA expression of PCNA was signi cantly decreased in miR-340 mimics group but was signi cantly increased in the group of miR-340 mimics + pcDNA3.1-Glut-1. In contrast, as for the apoptosis protein Bax, its mRNA expression was signi cantly increased in the group of miR-340 mimics but decreased in the group of miR-340 mimics +pcDNA3.1-Glut-1.…”

Polyphenols in cancer prevention: New insights (Review)

“…Polyphenols, including EGCG, CUR and RES, are known to exert an antioxidant effect; however, under certain conditions, they can be genotoxic for tumor cells. A study conducted by Almeida et al (57) evaluated the antitumor activity of RES and its possible mechanisms of action in bladder cancer cells with a different state of the TP53 gene. This gene responds to stress signals inducing cell cycle arrest, apoptosis, senescence and DNA repair; its mutations are the most common alterations in bladder cancer cells and are correlated with poor prognosis and recurrence.…”

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

“…Downregulation of Akt, mTOR and SRC expression, regulation of DNMT1 expression and an increased rate of cell death was reported in wild type P53 cells. Cell cycle arrest at S phase occurred in mutated TP53 cells while HOXB3/RASSF1A pathway modulation along with PCNA levels reduction in nucleus occurred in the highest‐grade cells [ 102 ].…”