Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death

Le-Niculescu, Helen; Bonfoco, Emanuela; Kasuya, Yoshitoshi; Claret, François X.; Green, Douglas R.; Karin, Michael

doi:10.1128/mcb.19.1.751

Cited by 438 publications

(346 citation statements)

References 90 publications

(99 reference statements)

Supporting

Mentioning

318

Contrasting

Unclassified

Order By: Relevance

“…The lack of JNK activation in mutated cells correlated with suppression of guggulsterone-induced apoptosis; again suggesting the critical role of JNK. These results are in agreement with reports that JNK is required for apoptosis induced by TNFα [47], FasL [48], and TRAIL [49,50]. JNK activation is also needed for apoptosis induced by chemotherapeutic agents [51].…”

Section: Discussionsupporting

confidence: 93%

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

Shishodia

Sethi

Ahn

et al. 2007

Biochemical Pharmacology

121

119

View full text Add to dashboard Cite

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and, p27. Guggulsterone induced apoptosis as indicated by increase in the number of Annexin V-and TUNEL-positive cells, through the down-regulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase 8, bid cleavage, cytochrome c release, caspase 9 activation, caspase 3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and down-regulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and down-regulation of anti-apoptotic protein expression.

show abstract

Section: Discussionsupporting

confidence: 93%

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

Shishodia

Sethi

Ahn

et al. 2007

Biochemical Pharmacology

121

119

View full text Add to dashboard Cite

show abstract

“…The cooperative role of p38 and JNK/c-Jun pathway remained to be addressed. Although the result was previously suggested in two articles, in each the specificity of pharmacological agents is contestable: Le Niculescu et al used the p38 inhibitor SB202190 at high unspecific doses to also inhibit JNKs (Manthey et al, 1998;Le-Niculescu et al, 1999); Namgung and Xia used CEP1347 as a JNK inhibitor in cooperation with a p38 inhibitor (Namgung and Xia, 2000), but CEP1347 has since been shown to affect mixed lineage kinase family rather than directly JNKs (Maroney et al, 2001). In this study we have employed an alternative approach using p38 kinase inhibitor SB203580 and DNcJun.…”

Section: Discussionmentioning

confidence: 97%

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Willaime‐Morawek¹,

Brami‐Cherrier²,

Mariani³

et al. 2003

Neuroscience

View full text Add to dashboard Cite

“…Later studies revealed that, in addition to enhanced cJun expression, phosphorylation of c-Jun by JNK is necessary for the apoptotic response in certain neuronal cell types, including cerebellar granule and sympathetic neurons (Le-Niculescu et al, 1999;Watson et al, 1998). The most conclusive evidence for the importance of JNK activation and c-Jun phosphorylation for neuronal apoptosis in the animal has been obtained in gene targeting experiments (Table 1).…”

Section: Jun As a Mediator Of Apoptosismentioning

confidence: 99%

“…The mechanism by which JNK3 and c-Jun promote apoptosis remains obscure. A candidate e ector is Fas ligand, which is induced in response to NGF withdrawal and JNK activation in PC12 cells (Le-Niculescu et al, 1999). Other mediators of JNK signaling during apoptosis could be p53 and the apoptotic protein Bax (Aloyz et al, 1998).…”

Section: Jun As a Mediator Of Apoptosismentioning

confidence: 99%

Diverse functions of JNK signaling and c-Jun in stress response and apoptosis

1999

View full text Add to dashboard Cite

Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death

Cited by 438 publications

References 90 publications

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Diverse functions of JNK signaling and c-Jun in stress response and apoptosis

Contact Info

Product

Resources

About