Étude des voies de signalisation et des mécanismes moléculaires impliqués dans [l']apoptose des cellules leucémiques HL-60 traitées avec des inhibiteurs de topoisomérases I et II
Notice bibliographique
Résumé
Chemotherapeutic agents, including camptothecin (CPI) and etoposide (VP1 6), which have been commonly used for cancer treatment for several years.Surprisingly, the exact molecular mechanisms of apoptosis activation induced by these drugs are flot fully characterized.In these studies, we have investigated the importance of some signaling pathways, including those associated with celi death receptors, the MAPKs and protein kinase Abi, in chemotherapy-induced apoptosis using' human leukemia celi unes as models.By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the ceil surface and the appearance of high molecular weight protein complexes primarily involving DR3, DR3 and DR4 after CPI and VP16 treatment in HL-60 celis, respectively.Both drugs failed to rapidly promote FAS aggregation in these ceils.In parallel, the expression level of DR3, DR4 and FAS remained mostly unchanged, while the expression of SODD and FLIP5, inhibitors of the ceil death receptor signaling pathways, decreased substantially 4 h after drug treatment.However, the high expression level of SODD or of dominant negative forms of FADD (FADD-DN) and DAP3 (DAP3-DN), or of the N-terminal deletion mutant of IRADD (IRADD-ND), achieved by transient transfection experiments, did not impair the kinetics of apoptosis after CPI and VP16 treatment in HL-60 and U937 ceils.Iaken together, these observations suggested that CPI and VP 16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, IRADD-ND and DAP3-DN.However, CPI or VP16 treatment in combination with TRML, a DR4 and DR5 ligand, substantially accelerated the kinetics of apoptosis more than treatment with CPI, VP16 or IRAIL alone.In contrast, co-treatment of CPI or VP16 with IWEAK or IL1A, putative DR3 ligands, did not facilitate apoptosis in HL-60 ceils.Ihese fmdings suggest that DR4 aggregation mediated by CPI or VP16 could represent a mean that accelerates TRAIL-induced apoptosis (Bergeron et aï.Mol Cancer Ther 2004, 3(12):1-11).Investigating the importance of the MAPK pathways, we found that both drugs failed to activate MKK3, MKK4 and JNK kinases while p38 was rapidly activated following CPI or VP16 treatment in HL-60.p38 activation appears to be independent of ceil death receptor signaling pathways since it was flot impaired by overexpression of fADD-DN or TRADD ND.In addition, celis treated with CPI in the presence of p38 inhibitors showed increased DNA fragmentation associated with apoptosis compared to celis treated with CPI only.Ihese resuits suggest that p38 activation is coupled to antiapoptotic or survival signaling in CPT-treated ceils.The significance of p38 activation in VP16-treated celis remains enigmatic.In parallel, expression of hcB(SR), an inhibitor of NF-KB activation, increased the kinetics of DNA fragmentation in CPI-treated celis.These resuits indicate that NF-icB activation could be involved in antiapoptotic or survival signaling in HL-60 ceils, in a way similar to that mediated by p38.However, the relationship between p38 and NF-cB activation remains to be investigated.AbI is rapidly activated by both drugs, and HI-60 ceils treated with Abi inhibitor showed reduced kinetics of DNA fragmentation in CPT-treated ceils, whule no DNA fragmentation variation was observed afier VP16 treatment.Thus, Abi activation appears to be associated with signaling that favours CPI-induced apoptosis in these ceils.However, the presence of PKC-inhibitor and of the natural isoforms of p73 and p63 ffiat show N-terminal deletions winch act as dominant negative forms (zs.Np73Œ-t3; ANp63a-), does flot impair the kinetics of apoptosis induced by CPI in HI-60 ceils.Ihese resuits suggest that Abi signaling afier CPI treatment acts independently ofthese pathways.Ihe work presented here indicates that HL-60 ceils treated with CPI or VP1 6 simultaneously induce different signaling pathways.Indeed, Abi activation leads to signaling that accelerates CPI-induced apoptosis in these cancer celis.In parallel, p38 and NF-icB activation is involved in survival signaling that reduces the kinetics of CPI-induced apoptosis in HI-60 celis.Finally, celi death receptor signaling pathways could act as an alternative mechanism or amplification ioop, and accelerate the kinetics of apoptosis in combined treatment involving IRAIL with CPI or V? 16.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».