Inhibition of JNK signaling diminishes early but not late cellular stress‐induced apoptosis

Abstract

The human leukemic T-cell line Jurkat was used to define the role of the cellular stress pathway with its key player kinase JNK in cancer therapy-induced apoptosis. JNK activity was inhibited by stable transfection with a dominant negative mutant of the upstream kinase JNKK/MKK4 or with the novel, potent and selective JNK1, -2 and -3 inhibitor SP600125. Inhibition of JNK activity delayed the onset of apoptosis induced by cisplatin, doxorubicin, ␥-irradiation and CD95-L but did not prevent apoptosis per se. Early events during apoptosis such as induction of CD95-L, activation of caspase-8 and exposure of phosphatidylserine on the cell surface were strongly inhibited. Also, at early time points of apoptosis, loss of the mitochondrial membrane potential and release of cytochrome c were markedly impaired. However, late signaling events during apoptosis such as cleavage of PARP and DNA fragmentation apoptosis were only marginally affected. These findings are in accordance with the activity of initiator and effector caspases. Whereas activity of the initiator caspase-8 was strongly inhibited early and late after induction, an inhibition of caspase-3 activity was only observed early after induction of apoptosis. We therefore suggest that cellular stress signaling contributes to the initiation of apoptosis, whereas it might be dispensable for the progression of apoptosis. Dysfunction of this pathway under pathological conditions might contribute to therapy resistance of cancer cells.

α2β1 Integrin Promotes Chemoresistance against Doxorubicin in Cancer Cells through Extracellular Signal-regulated Kinase (ERK)

“…Indeed, we found that doxorubicin-induced down-regulation of Mcl-1 levels is mediated via JNK and that ColI inhibited doxorubicin-induced JNK activation. Our results showed that JNK is important for doxorubicin-induced caspase activation and apoptosis in T-ALL cells, which is in line with previous studies (29,33). In addition, JNK has also been involved in the degradation of Mcl-1 through its phosphorylation and ubiquitination, a pathway that has recently been shown to play a key role in the sensitization of breast cancer cells to TRAIL by antimicrotubules agents (47) and in the synergy between the Bcl-2 pan-inhibitor ABT-737 and retinamide in the apoptosis of lymphoblastic leukemia cells (48).…”

“…ColI Inhibits Doxorubicin-induced JNK Activation-Previous studies have shown that JNK is involved in doxorubicin-induced apoptosis of T-ALL cells (29,33) and that Mcl-1 stability and levels can be regulated by JNK (34). Thus, we considered the possibility that doxorubicin reduces Mcl-1 levels through a mechanism involving JNK, and that ColI could restore Mcl-1 levels by blocking JNK activation.…”

Epstein‐Barr virus‐encoded latent membrane protein 1 promotes stress‐induced apoptosis upstream of caspase‐2‐dependent mitochondrial perturbation

“…Moreover, Debatin et al have shown that inhibition of JNK activity delays the onset of apoptosis induced by cellular stress (including cisplatin and doxorubicin) in a Jurkat T cell model. 40 Therefore, we propose, on the basis of the current data as well as recent data obtained in other model systems, that LMP1 may potentiate caspase activation and mitochondrial damage through its CTAR2 domain, potentially via JNK-dependent pathways (Fig. 5d).…”

Inhibition of Wnt-1 Signaling Induces Apoptosis in β-Catenin-Deficient Mesothelioma Cells

“…Recently, the JNK inhibitor has been shown to inhibit chemotherapyinduced apoptosis, at least in part, through the inhibition of caspase-3 activity (31). In this study, this small molecule inhibitor of JNK inhibits significantly the apoptotic cell killing induced by Wnt-1 siRNA, anti-Wnt-1 monoclonal antibody, or Dvl siRNA (Fig.…”