Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Abstract

Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.

Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways

“…In this study, the activation of MAPK by stress-inducing agents promoted an increased level of phosphorylated H2AX, a marker of DNA damage caused by double-strand breaks [54], as demonstrated previously in other cellular systems [19][20][21][22]55,56]. actions as sensors of DNA strand break sites [57].…”

“…In situations of cellular stress, such as serum starvation, specific isoforms of MAPK are closely regulated [21]. In addition, following the exposure of cervical cancer cells to IR, such as gamma radiation, apoptosis is triggered, as mediated by JNK, and p38 MAPK is activated, with opposite effects on regulation of the Bax, Bak and Bcl-2 proteins [22].…”

“…Three MAPKs have been implicated in the DNA damage response and repair pathways activated by different types of radiation stress that predominately function in regulating ATM or H2AX phosphorylation [19][20][21][22]. Thus, a role for DUSP3 in the maintenance of genomic stability has emerged, and new studies in this area may identify novel biological functions of this phosphatase.…”

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G2 DNA Damage Checkpoint in Human Cancer Cells

“…Our assertion that p38 plays a role in cell survival is supported by a number of recent reports linking this signaling pathway to increased levels of BCL2 and BCL-x l in response to DNA damage and stress (12,23). Furthermore, the chemical inhibition of p38 has been strongly associated with increased chemosensitivity in cancer cells (16,30).…”

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

“…In colorectal cancer cells, a novel cell type-specific role of p38α MAPK is found to control and mediate autophagy (Kim et al 2008a). Either autophagy or apoptosis has been found to be regulated by JNK-mediated Bcl-2 phosphorylation (Kim et al 2008b). Wei et al reported that JNK1-mediated Bcl-2 phosphorylation interferes with its binding to the proautophagy BH3 domain-containing protein Beclin 1, and had a dual role in autophagy and apoptosis regulation (Wei et al 2008).…”