Autoactivation of Procaspase-9 by Apaf-1-Mediated Oligomerization

Srinivasula, Srinivasa M.; Ahmad, Manzoor; Fernandes-Alnemri, Teresa; Alnemri, Emad S.

doi:10.1016/s1097-2765(00)80095-7

Cited by 1,011 publications

(810 citation statements)

References 38 publications

Supporting

Mentioning

761

Contrasting

Unclassified

Order By: Relevance

“…However, caspase-3-de®cient cells still activated caspase-9, although to a weaker extent than caspase-3 expressing cells. Our observations are also supported by recent in vitro studies, in which it was shown that caspase-9 cleaves directly caspase-3 and -7, but is unable to process caspase-6 (Srinivasula et al, 1998). In addition, depletion of caspase-3 from cell extracts abolished cytochrome c-induced processing of caspase-8 (Slee et al, 1999).…”

Section: Discussionsupporting

confidence: 90%

“…Activation of initiator caspases is mediated by binding of adaptor molecules to protein interaction motifs in their prodomains. Two general types of interaction have been identi®ed (Martin et al,1998;Muzio et al, 1998;Srinivasula et al, 1998). Procaspase-8 and -10 each contain two tandem death e ector domains (DEDs), while procaspase-1, -2, -4 and -9 contain a caspase recruitment domain (CARD).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

View full text Add to dashboard Cite

Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either de®cient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-x L prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less e ective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Accordingly NPA cells were treated with sTRAIL in the presence or absence of CHX for 8 h. MCF-7, a TRAIL-sensitive cell line was used as a positive control. As shown in Figure 4b, caspase-9 activation in NPA was higher in the presence of CHX after 8 h. The increase in the activation of caspase-9 can be judged by the appearance of p37 band of caspase-9 (Figure 4b) that results from cleavage of caspase-9 at Asp 330 by active caspase-3 (Srinivasula et al, 1998). Similar acceleration in caspase-8 activation was also observed after TRAIL treatment in combination with cycloheximide (data not shown).…”

Section: Caspase Activation and Cleavage Of Dffmentioning

confidence: 84%

TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention

Ahmad

Shi

2000

Oncogene

Self Cite

View full text Add to dashboard Cite

To determine whether the apoptotic machinery of thyroid cancer cells is functional and could be activated for tumoricidal purposes, we examined the apoptosis induced by the cytokines TNF-a, Fas and TRAIL in thyroid cancer cell lines, NPA and SW579. Interestingly, out of these cytokines, only TRAIL was able to trigger signi®cant apoptosis. The tumoricidal e ect of TRAIL was further enhanced by CHX, suggesting the presence of CHX-sensitive inhibitor(s) of apoptosis in these thyroid cancer cell lines. The anti-apoptotic proteins like FLAME-1, Bcl-2 and Bcl-xL are believed to be such CHX-sensitive inhibitors in various types of cancer cells. We, however, provide the evidence using NPA and SW579 cell lines that these proteins were not a ected by the CHX treatment in thyroid cancer cells. The apoptosis of thyroid cancer cells was mediated by the classical activation of caspases that in turn activated the DNA Fragmentation Factor (DFF-45). To elucidate the role of individual caspases in TRAIL-mediated apoptosis, the inhibitory e ects of several general and speci®c tetrapeptide caspase inhibitors were studied. The inhibitors of caspase-1, -6, -8, and -9 as well as general upstream inhibitors of apoptosis could dramatically inhibit TRAIL-induced apoptosis in thyroid cancer cells. Caspase-2 and -3 inhibitors, on the other hand, had no signi®cant e ect. When the cells were treated with either agonistic Fas antibody (CH11) or TNF-a, no apoptotic changes were observed. The apoptosis induced by agonistic Fas Ab could be seen only after a prolonged exposure (24 h) to CHX, whereas TNF-a had no e ect even in the presence of CHX. The e cacy of TRAIL was also tested on other types of thyroid cancer cells like ARO, FRO (anaplastic carcinoma) and TPC-1 (papillary carcinoma) and compared to that triggered by other death inducing cytokines FasL and TNF-a. Again TRAIL was more potent in triggering apoptosis than Fas and TNF-a. Since TRAIL is e ective in selectively killing thyroid tumor cells without a ecting normal thyrocytes and also does not cause organ toxicity and in¯ammation in vivo, its potential for the treatment of thyroid cancer seems very promising.

show abstract

“…However, the mechanism by which guggulsterone activates caspase-8 is not clear. Several reports indicate that auto-activation induced by oligomerization can activate caspase-8 [40,41]. Thus, it may be possible that guggulsterone induces the oligomerization of caspase-8.…”

Section: Discussionmentioning

confidence: 99%

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

110

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

Autoactivation of Procaspase-9 by Apaf-1-Mediated Oligomerization

Cited by 1,011 publications

References 38 publications

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention

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

Contact Info

Product

Resources

About