Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells

Abstract

The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1 Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21 Cip-1/WAF1 via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the speci®c MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased *sixfold 60 min after irradiation. In the presence of MAP kinase blockade by PD98059 the ability of a single 1 Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24 ± 48 h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4 ± 8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizng radiation. Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death in vitro.

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

“…We have proposed a scheme to illustrate the manner in which FGF2 predominantly activates ERK2 and stimulates sustained FGF1 and Bcl-x production (Figure 8). The importance of the long-term activation of ERK2 for cell survival is consistent with studies showing that acute activation of the ERK cascade by growth factors potentiates proliferation whereas a chronic increase in ERK activity is cytoprotective (Carter et al, 1998). In addition, it was shown that overproduction of ERKs in human breast cancer was required for cell survival (Sivaraman et al, 1997) and that cell survival is correlated with the overproduction of ERK2 during aging of RPE cells (Guillonneau et al, 1998b).…”

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

“…However, the mechanisms by which radiation can either increase cell death or alter the proliferative rate of surviving cells are not understood. Recently, radiation has been shown to activate multiple signaling pathways within cells which can alter cell survival or proliferation depending upon the radiation dose, the cell type, and the culture conditions (Carter et al, 1998;Xia et al, 1995;Chmura et al, 1997;Santana et al, 1996). Several groups have shown that the epidermal growth factor receptor (EGFR, also called ErbB1) is activated in response to irradiation of squamous and mammary carcinoma cells (Carter et al, 1998;Schmidt-Ullrich et al, 1997;Kavanagh et al, 1998;Balaban et al, 1996;Dent et al, 1999).…”

Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines

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