The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells

Abstract

Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

“…The ERK1/2 and p38 MAPK signaling pathways can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines (Baccarini 2005;Meloche and Pouysségur 2007;Roux and Blenis 2004) and are important targets in the diagnosis and treatment of cancer (Roberts and Der 2007). Suppression of the activated EGFR and ERK1/2 and p38 MAPKs as well as Akt signaling pathways led to inhibition of the proliferation of A549 cells (Baldys et al 2007;Nguyen et al 2004;Recchia et al 2009;Su et al 2010). There has been the cross-talk in EGFR and c-Met pathways in A549 cells which is related to the A549 cell proliferation (Puri and Salgia 2008).…”

Deltonin Isolated from Dioscorea zingiberensis Inhibits Cancer Cell Growth through Inducing Mitochondrial Apoptosis and Suppressing Akt and Mitogen Activated Protein Kinase Signals

“…The inhibition of either the MAPK pathway or Akt activation has been shown to induce apoptosis in tumor cells. [20][21][22] Hence, to determine whether Deltonin inhibits the growth of C26 cells and simultaneously promotes apoptosis by modulating the two pathways, we observed changes in the phosphorylation of ERK 1/2 and Akt after Deltonin treatment. With different concentrations of Deltonin (0, 0.8, 1.6, 3.2 mM) for 48 h, we observed a dose-dependent decrease of phosphorylation of both ERK 1/2 and Akt (Fig.…”

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

“…Furthermore, oxidative stress has been shown to activate ERK as a protective mechanism (Guyton et al, 1996;Aikawa et al, 1997;Bhatt et al, 2002). However, a proapoptotic role has been demonstrated for ERK in several studies with different stimuli, including anticancer drugs (Stanciu et al, 2000;Wang et al, 2000;Guise et al, 2001;Xiao and Singh, 2002;Lee et al, 2003;Zhang et al, 2003;Nguyen et al, 2004).…”