Ubiquitin-Activating Enzyme E1 Inhibition Caused Acute Leukemia Cell Apoptosis By Affecting CHOP Pathway
Notice bibliographique
Résumé
Abstract Background: The ubiquitin proteinase system is involved in the pathogenesis of blood malignant tumors. Preliminary study of our group found that increased serum ubiquitin activase E1 (UBE1) fragment were in newly diagnosed and refractory & relapsed acute myeloid leukemia (AML), and its relative intensity was negatively correlated with AML's remission process and prognosis. The inhibition of UBE1 activity can promote AML cell apoptosis and may be related to the mechanism of endoplasmic reticulum stress. The current study is to clarify the role and mechanism of endoplasmic reticulation-derived transcription factor CHOP in apoptosis of leukemia cells induced by inhibiting ubiquitin activase E1 (UBE1) activity. Methods: UBE1-shRNA lentivirus carrier and CHOP-siRNA plasmid co-infected leukemia cells (U937, K562, NB4, THP-1). The protein expression of antiapoptosis molecules, endoplasmic reticulum stress protein and death receptors (Bcl-2, TRB3, ERO1α, DR5 and Bax) were detected by Western Blot. MTT and flow cytometry were used to detect cell proliferation inhibition and apoptosis. The model of leukemia cell bearing nude mouse was constructed. UBE1-shRNA and/or CHOP-siRNA were injected into the tumor. The tumor size, lifetime changes and tumor pathological changes were observed. Western Blot and RT-PCR were used to detect endoplasmic reticulum stress molecules and apoptosis molecules. Results: Infection of UBE1-shRNA significantly inhibited proliferation of leukemia cells (U937, K562, NB4, THP-1), while the inhibition of UBE1-shRNA and CHOP-siRNA co-transfected leukemia cells was decreased (p=0.032). The apoptosis rate in UBE1-shRNA leukemia cells was lower than that in UBE1-shRNA and CHOP-siRNA co-transfected leukemia cells (p=0.026). UBE1-shRNA can reduce the expression of apoptosis molecule Bcl-2 and increase the expression of TRB3, ERO1α, death receptor DR5, Bax protein. CHOP-siRNA can increase the expression of Bcl-2 in leukemia cells and reduce the expression of TRB3, ERO1α, death receptor DR5 and Bax protein. shRNA-UBE1 inhibited the leukemia cell xenograft, while siRNA-CHOP reversed the growth inhibition of shRNA-UBE1 on leukemia cell xenograft (p=0.002). A larger number of leukemia cells were degenerative necrosis in the UBE1-shRNA group comparing with the UBE1-shRNA and siRNA-CHOP co-transfected groups (p=0.023), and damaged membrane, different sizes, blurred outline, and nuclear pyknosis and karyorrhexis could be observed. The average survival time of mice with co-transfection of shRNA-UBE1 and siRNA-CHOP was shorter than the average survival time of mice with shRNA-UBE1 (p=0.016). Compared with the shRNA-UBE1 group, there was no difference in expression of endoplasmic reticulum stress molecules in co-transfection of UBE1-shRNA and siRNA-CHOP group, but TRB3, ERO1α, DR5, Bax expression were decreased, and Bcl-2 was increased (p<0.05). Conclusion: The inhibition of UBE1 activity can induce AML cell apoptosis by endoplasmic reticulum stress CHOP pathway. It will provide new clues for the treatment of acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.
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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 | 0,000 |
| 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 | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».