| First Author | Roos J | Year | 2014 |
| Journal | Cancer Res | Volume | 74 |
| Issue | 18 | Pages | 5244-55 |
| PubMed ID | 25082812 | Mgi Jnum | J:215984 |
| Mgi Id | MGI:5607458 | Doi | 10.1158/0008-5472.CAN-13-3012 |
| Citation | Roos J, et al. (2014) 5-Lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia. Cancer Res 74(18):5244-55 |
| abstractText | Nonsteroidal anti-inflammatory drugs such as sulindac inhibit Wnt signaling, which is critical to maintain cancer stem cell-like cells (CSC), but they also suppress the activity of 5-lipoxygenase (5-LO) at clinically feasible concentrations. Recently, 5-LO was shown to be critical to maintain CSC in a model of chronic myeloid leukemia. For these reasons, we hypothesized that 5-LO may offer a therapeutic target to improve the management of acute myeloid leukemia (AML), an aggressive disease driven by CSCs. Pharmacologic and genetic approaches were used to evaluate the effects of 5-LO blockade in a PML/RARalpha-positive model of AML. As CSC models, we used Sca-1(+)/lin(-) murine hematopoietic stem and progenitor cells (HSPC), which were retrovirally transduced with PML/RARalpha. We found that pharmacologic inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARalpha-expressing HSPCs. Through small-molecule inhibitor studies and genetic disruption of 5-LO, we also found that Wnt and CSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders nuclear translocation of beta-catenin. Overall, our findings revealed that 5-LO inhibitors also inhibit Wnt signaling, not due to the interruption of 5-LO-mediated lipid signaling but rather due to the generation of a catalytically inactive form of 5-LO, which assumes a new function. Given the evidence that CSCs mediate AML relapse after remission, eradication of CSCs in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in patients with AML. Cancer Res; 74(18); 5244-55. (c)2014 AACR. |
