Effect of inhibition of MEK pathway on 5-aza-deoxycytidine-suppressed pancreatic cancer cell proliferation

Abstract

ABSTRACT. Pancreatic adenocarcinoma is a lethal disease because it is inoperable at the time of diagnosis. Therefore, the search for new therapeutic approaches is critical. The abnormal expression of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway and alteration in epigenetic modification (DNA methylation and acetylation of histones) is a common feature in the majority of human pancreatic adenocarcinomas. Because DNA methyltransferase levels are regulated by the MEK pathway, we examined the effects of an MEK inhibitor, PD98059, on the action of DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC), the epigenetic agent in the pancreatic cell line CFPAC1. Our results showed that PD98059 significantly potentiated the capability of 5-azadC to induce a cessation of cell proliferation concomitant with cell cycle arrest. We also observed an increase in tumor suppressor gene expression associated with the efficacy of treatment with PD98059 and 5-aza-dC. Further studies explored the molecular mechanisms by which . We found that 5-aza-dC induced acetylation of histone H3 on the p21 WAF1 gene promoter and demethylation status on the p21 WAF1 gene promoter region. These effects were strikingly enhanced by the concomitant blockade of the MEK pathway. Furthermore, knockdown of p21 WAF1 by small interfering RNA rescued human pancreatic cancer cells from 5-aza-dC-mediated growth inhibition. Taken together, our results show that the MEK inhibitor enhanced the effects of 5-aza-dC in human pancreatic cancer cells. These results suggest that the MEK signal pathway may be a potential target for pancreatic cancer therapy.

DNA methylation inhibitor, decitabine, promotes MGC803 gastric cancer cell migration and invasion via the upregulation of NEDD4-1

“…The results revealed that 1 µM DAC significantly promoted the invasion and migration of the MGC803 cells, although it failed to elicit a response in the SGC7901 gastric cancer cell line. Consistently with previously published studies (31,32), DAC inhibited the proliferation of each cell line, without any marked difference in its effectiveness (Fig. 1C).…”

Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells

“…More recently, 5-AZA-dC was tested in an aggressive stroma-rich mouse model of pancreatic adenocarcinoma 43 . Wang and coworkers also showed that the MEK inhibitor PD98059 potentiated the capability of 5-AZA-dC to mediate growth arrest in pancreatic cancer cells 44 . Currently, a phase II trial is recruiting participants to determine the effect of 5-AZA (oral azacytidine) on progression-free survival and outcomes in patients with resected pancreatic adenocarcinoma at high risk of recurrence 45 .…”

A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent

“…5-aza-2’deoxycytidine (DAC) has been tested in solid tumors including breast and gastric cancers, and PDAC; but as a monotherapy it has limited success [ 40 – 42 ]. DAC was used in combination either with a MEK inhibitor, Emodin, or IFN-gamma to successfully inhibit PDAC models [ 43 – 45 ]. Thus, additive inhibition was achieved with the use of epigenetic modulators and chemotherapy.…”