Distinctive regulation and function of PI 3K/Akt and MAPKs in doxorubicin‐induced apoptosis of human lung adenocarcinoma cells

Abstract

Regulation and function of PI 3K/Akt and mitogen-activated protein kinases (MAPKs) in doxorubicin-induced cell death were investigated in human lung adenocarcinoma cells. Doxorubicin induced dose-dependent apoptosis of human lung adenocarcinoma NCI-H522 cells. Prior to cell death, both Akt and the MAPK family members (MAPKs: ERK1/2, JNK, and p38) were activated in response to the drug treatment. The kinetics of the inductions for Akt and MAPKs are, however, distinct. The activation of Akt was rapid and transient, activated within 30 min of drug addition, then declined after 3 h, whereas the activations of three MAPKs occurred later, 4 h after addition of the drug and sustained until cell death occurred. Inhibition of PI 3K/Akt activation had no effect on MAPKs' activation, suggesting that the two pathways are independently activated in response to the drug treatment. Inhibition of PI 3K/Akt and p38 accelerated and enhanced doxorubicin-induced cell death. On the contrary, inhibition of ERK1/2 or JNK had no apparent effect on the cell death. Taken together, these results suggest that PI 3K/Akt and MAPKs signaling pathways are all activated, but with distinct mechanisms, in response to doxorubicin treatment. Activation of PI 3K/Akt and p38 modulates apoptotic signal pathways and inhibits doxorubicin-induced cell death. These responses of tumor cells to cancer drug treatment may contribute to their drug resistance. Understanding of the mechanism and function of the responses will be beneficial for the development of novel therapeutic approaches for improvement of drug efficacy and circumvention of drug resistance.

The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1

“…This is in agreement with the study by Zhao et al (2004) showing that the MAPK pathway is not involved in doxorubicininduced apoptosis of lung adenocarcinoma cells (Zhao et al, 2004). The effects of various cytotoxic agents may vary considerably depending on the cell type and the signalling pathway activity (Wang et al, 2000;Guise et al, 2001;Liu et al, 2001).…”

“…Activation of Ras signalling pathways is associated with the upregulation of target genes involved in drug transport (Chin et al, 1992;Zuber et al, 2000). Drug treatment may downregulate or activate signalling kinases, respectively (Nakashio et al, 2002;Zhao et al, 2004). Most importantly for the issue of therapy, enhanced sensitivity to drug treatment was observed in the presence of signalling inhibitors.…”

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

“…These findings agree well with recent studies showing that p38 MAPK is activated by doxorubicin and is required for doxorubicin-induced apoptosis in fibroblasts and cardiomyocytes [45][46][47], although possible involvement of Bcl-2 proteins was not considered in those investigations. Nevertheless, other researchers [48] found no change in p38 MAPK activity in breast cancer cells treated with doxorubicin, and it has been suggested that p38 MAPK protects lung cancer cells from apoptosis caused by doxorubicin [49]. Our data show that p38 MAPK mediates doxorubicin-induced endothelial apoptosis by inhibiting phosphorylation of Bad in a PI3-K/Akt-dependent manner and by downregulating Bcl-xL.…”

Dose–response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

“…We find that AF induces Akt phosphorylation at serine 473 (Figure 4a), which is required for Akt activity (Shieh et al, 2000;Sordet et al, 2003;Sarbassov et al, 2005). Akt has been shown to be activated in response to a wide variety of growth factors, such as insulin or insulinlike growth factor I (IGF-1), but also in response to DNA damage (Fang et al, 2001;Zhao et al, 2004;Viniegra et al, 2005). Constitutive activation of Akt has been shown to mediate resistance to chemotherapy or radiotherapy (Knuefermann et al, 2003).…”