MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells

Abstract

MEK/ERK-mediated signals have recently been found to inhibit Fas-mediated cell death through inhibition of caspase-8 activity. It remains unknown whether MEK/ERK-mediated signals affect ionizing radiation (IR)-induced cell death. Here we demonstrate that MEK/ERK-mediated signals selectively inhibit IR-induced loss of mitochondrial membrane potential (DC m ) and subsequent cell death. In Jurkat cells, TPA strongly activated ERK and inhibited the IR-induced caspase-8/Bid cleavage and the loss of DC m . The inhibitory effect of TPA was mostly abrogated by pretreatment of a specific MEK inhibitor PD98059, indicating that the effect depends upon MEK/ERKmediated signals. Moreover, BAF-B03 transfectants expressing IL-2 receptor (IL-2R) bc chain lacking the acidic region, which is responsible for MEK/ERK-mediated signals, revealed higher sensitivity to IR than the transfectants expressing wildtype IL-2R. Interestingly, the signals could neither protect the DC m loss nor cell death in UV-irradiated cells. These data imply that the anti-apoptotic effect of MEK/ERK-mediated signals appears to selectively inhibit the IR-induced cell death through protection of the DC m loss. Our data enlighten an antiapoptotic function of MEK/ERK pathway against IR-induced apoptosis, thereby implying its contribution to radioresistance.

Prognostic Associations of Activated Mitogen-Activated Protein Kinase and Akt Pathways in Glioblastoma

“…One study (8) indicated that adding PD98059 (prevents MAPK phosphorylation) to monocytic leukemia cells prolonged the G 2 -M phase (the most radiosensitive time of the cell cycle) and increased radiation-induced cell killing. It was also shown in leukemia cells that MAPK inhibits radiation-induced apoptosis by preventing caspase-8/Bid cleavage and the loss of mitochondrial membrane potential, which are important early apoptotic events (34). Within the U87 glioma cell line, MAPK was found to contribute to radiation induction of the early growth response gene (Egr-1) promoter (35).…”

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

“…Several authors have shown that MAPK pathway protects from apoptosis triggered by different stimuli at the level of mitochondria. 33,34 MCF-7 cells, which are deficient in caspase-3 expression, 20 have been ascribed to the type II group of cells since they require the mitochondrial pathway for death receptor-mediated apoptosis signaling. 4 Moreover, we have observed that overexpression of Bcl-2 in MCF-7 cells not only blocks CD95 mediated apoptosis 21 but also TRAIL-mediated cell death.…”

Radiation-induced cell signaling: inside-out and outside-in

“…In cell lines where PI3K regulates radiosensitivity, inhibition of the ERK1/2 pathway did not significantly alter the radiosensitivity of cells, in agreement with data in HCT116 cells. ERK1/2 signaling has often been stated to play no role in controlling radiosensitivity; in some cell lines, inhibition of ERK1/2 has been linked to protection from radiation toxicity (103,104).…”