Inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) Selectively Kills Acute Myeloid Leukemia Cells
Notice bibliographique
Résumé
Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, developing novel and selective anti-AML therapies are needed. Our group recently identified 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid commonly found in the Papaveraceae family, as a novel and selective anti-AML drug that binds to and inhibits peroxisome proliferation-activated receptor delta (PPARδ). PPARδ, along with the other two PPAR isoforms, PPARα and PPARγ, belongs to a family of ligand-dependent transcription factors that regulate a variety of important genes involved in various biological pathways, including glucose and lipid homeostasis, inflammation, proliferation, and differentiation. While PPARα and PPARγ have been extensively characterized in leukemia, little is known about PPARδ. Here, we show that 6ME is a novel and selective anti-AML molecule that targets the PPARδ-FAO pathway, suggesting PPARδ may be a potential therapeutic target for AML treatment. 6ME suppressed clonogenic growth of patient-derived AML cells (IC50: 2.025 ± 0.187 μM) while having no effect on normal hematopoietic cells. In mouse engraftment studies, where patient-derived AML cells are engrafted into the mouse bone, 6ME (5 mg/kg, three times/week for 4 weeks) was given after a 3-week post-transplantation of patient cells into immunocompromised mice, once bone marrow aspirate engraftment was confirmed. The subsequent 4-week treatment with 6ME significantly reduced patient-derived AML cell engraftment in mouse bone marrow by about 45% (p<0.0001) without imparting toxicity. Using published computational methods, the family of PPAR transcription factors were identified as potential targets of 6ME. To confirm this potential mechanism, cell-based luciferase reporter assays, immunoblotting and co-immunoprecipitation (co-IP) coupled with ultra-high performance liquid chromatography (UHPLC) assay were performed to confirm that 6ME bound to PPARδ and inhibited its activity. To further study this interaction, we quantified downstream targets of PPARδ-transcriptional activity in 6ME-treated AML cells by immunoblotting; this showed that PPARδ-related genes including CD36, CPT2, UCP3, and PPARδ itself were significantly reduced by 6ME. Finally, shRNA-mediated PPARδ knockdown (KD) AML cells were created to probe the functional impact of PPARδ in AML cells. As expected, PPARδ KD AML cells were much less sensitive to 6ME, and those cells with reduced PPARδ resulted in a similar pattern of protein changes to that of 6ME-treated cells. As 6ME reduced levels of CD36, CPT2, UCP3, and PPARδ, which are all essential proteins involved in fatty acid oxidation (FAO), we measured FAO in AML cells using high-resolution respirometry. When provided with an FAO substrate (palmitate-BSA), 6ME significantly hindered oxygen flux of intact AML cells, indicating that 6ME impairs FAO-supported mitochondrial respiration. Similarly, treatment with a PPARδ antagonist (i.e., GSK0660) but not an agonist (i.e., GW0742), also resulted in the inhibition of FAO-supported intact AML cell respiration, suggesting 6ME targets PPARδ to impair mitochondrial FAO. Taken together, our 6ME targets the PPARδ-FAO pathway and may open a new avenue for therapeutic targeting in the treatment of AML.
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 | 0,000 |
| 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) | 0,001 | 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 ».