Novel Fatty Acid Oxidation Inhibitor Avocatinb Induces AMPK-Dependent Apoptosis of AML Cells Co-Cultured with BM-Adipocytes
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".