E-selectin is an endothelial adhesion molecule important in the recruitment of leukocytes to the bone marrow and inflammatory tissues; moreover, it has also been implicated in cancer metastasis and as a critical mediator of chemoresistance. This study investigated the effects triggered by the binding of E-selectin on acute myeloid leukemia (AML) cell lines regarding the activation of significant signaling pathways and their impact on biological functions. We observed that upon treatment with a recombinant E-selectin construct on AML cells, there was an activation of the AKT/NF-κB pathways, which are known to be central regulators of many cellular processes, including survival and proliferation. We found that the E-selectin-mediated activation varied in rate and amplitude among AML cell lines spanning differentiation blockage at different stages. Furthermore, we found that E-selectin binding in HL-60 and KG1-a cells sensitized the cells to daunorubicin (DNR), a chemotherapy drug commonly used to treat AML. The observed chemosensitivity could be linked to the decrease of Aldo Keto Reductases (AKR) protein levels upon E-selectin treatment, which is known to metabolize DNR and reduce its cytotoxicity. Additionally, we explored the role of exosomes as a regulator of the generation of therapy resistance by examining the effects treatment with KG1-a derived exosomes, a cell line that exhibits higher chemoresistance compared to other AML cell lines, had on viability in HL-60 cells upon chemotherapy. We found that even in the absence of KG1-a cells, exosomes were sufficient to provide an increase in chemoresistance. Overall, these studies explore properties exerted by AML cells that could lead to further understanding of AML and thus the development of potential therapeutic targets to overcome challenges currently found in the treatment of this disease.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/679938 |
| Date | 07 1900 |
| Creators | Lopez Madrigal, Gloria |
| Contributors | Merzaban, Jasmeen, Biological and Environmental Science and Engineering (BESE) Division, Rosado, Alexandre S., Gadhoum, Samah Z. |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | 2023-07-28, At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis will become available to the public after the expiration of the embargo on 2023-07-28. |
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