pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression

Abstract

BackgroundOur previous study has demonstrated that knockdown of activated ERK1/2(pERK1/2) sensitizes pancreatic cancer cells to chemotherapeutic drug gemcitabine (Gem) treatment. However, the details of this survival mechanism remain undefined. It has also shown that Bcl-2 confers resistance and Bax sensitizes to gemcitabine-induced apoptosis in pancreatic cancer cells. Furthermore, the extracellular signaling-regulated kinase (ERK) signaling pathway regulates Bcl-2/Bax expression ratio. We therefore tested the hypothesis that pancreatic cancer cells are resistant to gemcitabine and this resistance is due to activation of ERK1/2 and subsequent upregulation of Bcl-2 and downregulation of Bax.MethodsPancreatic cancer cell BXPC-3 was used in the study. The effect of pharmacological inhibition of ERK1/2 on resistance of pancreatic cancer cells to apoptosis induced by treatment with gemcitabine was analyzed. The following methods were utilized: TUNEL and ELISA were used to detect apoptosis. Western blot was used to detect the protein expression.ResultsGemcitabine treatment enhanced the activity of ERK1/2 in the BXPC-3 cells. Inhibition of the ERK1/2 by PD98059 could downregulate Bcl-2 and upregulate Bax and was associated with restoration of sensitivity to gemcitabine in BXPC-3 cells. Depletion of endogenous Bcl-2 expression by specific small interfering RNA transfection significantly increased gemcitabine-induced cell apoptosis. Combined treatment with PD98059 and Bax siRNA transfection could decrease gemcitabine-induced ERK1/2 and Bax activation, which subsequently resulted in decreased apoptosis.ConclusionsThe upregulation of ERK1/2-dependent Bcl-2 and downregulation of ERK1/2-dependent Bax can protect human pancreatic cancer cells from gemcitabine-induced apoptosis. Targeting the ERK1/2-Bax/Bcl-2 pathway may in part lead to sensitization of pancreatic cancer to gemcitabine.

Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction

“…We sought to determine whether FBP1 E4 can restore gemcitabine sensitivity in PDAC cells through inhibition of pERK1/2. In agreement with the findings in the BXPC-3 PDAC cell line (27) and RAS mutation–induced mouse PDAC tumors (29), we found that the mean value of pERK1/2 staining was relatively higher in gemcitabine-treated PDAC patient specimens compared with that in untreated counterparts (Supplementary Fig. S1B and S1C).…”

“…However, it fails to significantly improve the outcome of pancreatic carcinoma patients due to acquisition of chemoresistance in most tumor cells (26). It is well documented that gemcitabine treatment results in activation of the RAS–RAF–MAPK pathway (27). However, the mechanism underlying gemcitabine-induced MAPK activation remains poorly understood.…”

Low concentration of formononetin stimulates the proliferation of nasopharyngeal carcinoma cell line CNE2 by upregulating bcl-2 and p-ERK1/2 expression

“…Thus, low concentrations of formononetin may significantly promote CNE2 cell proliferation through p-ERK upregulation. This process subsequently modulates the activity of downstream targets, including some members of the bcl-2 protein family (Wang et al 2015).…”

Restore of miR-541 resensitizes pancreatic cancer cells to gemcitabine-induced apoptosis through suppression of HAX-1

“…Gemcitabine belongs to the pyrimidine antineoplastic drugs. Its main metabolites can incorporate into the DNA of cancer cells, followed by breaking the normal function of DNA and thus activating the apoptotic pathway of cancer cells [6,7]. However, gemcitabine resistance is usually seen during the PCa treatment [8,9].…”