Novel Fatty Acid Oxidation Inhibitor Avocatinb Induces AMPK-Dependent Apoptosis of AML Cells Co-Cultured with BM-Adipocytes
Notice bibliographique
Résumé
Abstract Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), comprising approximately 60% of BM space in a 65-year old person. In BM environment, leukemia cells continuously adapt to deficient supply of nutrients and oxygen, acquiring quiescent and chemoresistant profiles. Fatty acid metabolism is one of the key energy pathways for AML survival (Samudio, J Clin Invest. 2010), and we previously demonstrated that AML cells activate oxidative phosphorylation and fatty acid oxidation (FAO) in the presence of BM-adipocytes (Tabe ASH 2015). These findings indicate the importance of FAO for AML cells survival under the adipocyte-abundant BM-microenvironment. A novel FAO inhibitor avocatinB, an odd-numbered carbon lipid derived from avocado fruit, has been recently shown to induce apoptosis and cell growth inhibition in AML cells (Lee, Cancer Res. 2015). In the present study, we investigated the molecular mechanisms of anti-leukemic effect of avocatinB in AML cells, utilizing THP1, OCI-AML3 and U937 AML cell lines co-cultured with human mesenchymal stem cells (MSC)-derived BM-adipocytes, mimicking the aging BM microenvironment. Treatment with avocatin B significantly induced ROS accumulation in U937 cells co-cultured with BM-adipocytes (MFI of ROS-sensitive dye; avocatinB (-) / (+); 164±50 / 581±85, p=0.04), whereas only minimum increase of ROS was observed in the absence of BM-adipocyte, indicating that avocatinB causes progressive oxidative damage in AML cells under the BM-adipocyte co-culture conditions. Of importance, avocatinB synergistically enhanced apoptotic effects of AraC in the presence of BM-adipocytes (combination index CI; adipocyte (-) / (+); THP1: 1.2 / 0.4, OCI-AML3: 0.7 / 0.3). Immunoblot analysis demonstrated that avocatinB activated the stress response kinase AMPK in THP1 and OCI-AML3 cells under BM-adipocyte co-culture conditions. AMPK is a crucial cellular energy sensor that regulates energy metabolism including FAO and gene transcription through mTOR inhibition. We therefore investigated the role of AMPK in avocatinB induced anti-leukemic effects on AML cells, utilizing AMPK knockdown (shAMPK) OCI-AML3 cells. shAMPK OCI-AML3 cells were significantly less sensitive to nutrient starvation-induced cell death in the absence of BM-adipocyte (p<0.01). While co-culture with BM-adipocytes protected control (nsAMPK) OCI-AML3 cells from spontaneous cell death, co-culture facilitated cell death of shAMPK cells. In turn, shAMPK OCI-AML cells were less sensitive to avocatinB compared to nsAMPKcells in the absence of BM-adipocyte with no additive/synergistic anti-proliferative effects of avocainB and AraC combination irrespective of the presence of BM-adipocytes (CI > 1.0). In nsAMPK cells, but not in shAMPKcells BM-adipocyte co-culture upregulated p-4EBP1 and cMyc expression which was abrogated by avocatinB and AraC combination treatment accompanied by induction of cleaved caspase 3. In summary, FAO inhibitor avocatinB induces pro-apoptotic effects through AMPK-dependent inhibition of mTOR signaling that disrupts energy homeostasis and induces ROS accumulation in AML cells under BM-adipocyte co-culture conditions. The ability of avocatinB to selectively enhance anti-leukemic effects of AraC in the presence of BM-adipocytes suggests that the strategies targeting FAO warrant further exploration in elderly AML patients. Disclosures Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.
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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) | 0,001 | 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 ».