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Characterization of the relationship between glutaminolysis and autophagy and their influence on acute myeloid leukemia cells
Portugal (PorMSIC) - University of Minho, Braga
Life and Health Sciences Research Institute (ICVS) Universidade do Minho Campus de Gualtar
Paula Ludovico and Belém Sampaio-Marques
English, Portuguese, Spanish
Type of Research Project
- Basic science
What is the background of the project?
Acute myeloid leukemia (AML) comprises a heterogeneous group of neoplasms characterized by an impaired differentiation and/or proliferation of immature progenitor’s cells. Studies demonstrated an important role of glutaminolysis in AML cells survival and proliferation. A crosstalk between glutaminolysis and autophagy has been described in other cancer cells but not in AML cells. This work aims to characterize glutaminolysis, disclose glutaminolysis-autophagy crosstalk and understand their impact on AML cell lines, HL-60, NB-4 and KG-1, response to chemotherapy. Intra- and extracellular glutamine/glutamate/ammonia levels, autophagy and cell viability will be evaluated after glutaminolysis manipulation. All the experiments will be done in the presence of cytarabine plus doxorubicin, the most common therapeutic drugs (5). With this project, we hope to get new insights on the AML pathophysiology and to contribute for the improvement of the current therapeutic approaches.
What is the aim of the project?
The project aims to investigate the role of glutaminolysis and its crosstalk with autophagy on the context of acute myeloid leukemia (AML) pathophysiology.
What techniques and methods are used?
As all projects, this one will start with design and preparation of the experiments. The project will determine the glutamine dependency of HL-60, NB-4 and KG-1 cells, evaluate the impact of glutaminolysis manipulations on autophagy and consequently, on AML cells viability and evaluate the impact of glutaminolysis manipulation on the cells response to conventional chemotherapy. To accomplish these steps, the project makes use of preparation of solutions/buffers, cell culture, Western blot analysis, Centrifugation and Flow cytometry. During the project, because of the pharmacological manipulation of the culture, it’s important to access the cell viability. To do so, the project will use annexin V/PI (Propidium Iodide) assay.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student is expected to accomplish the following tasks: evaluate the glutamine dependency of HL-60, NB-4 and KG-1 cells by depleting the culture medium of glutamine, pharmacological inhibition of glutaminase and of glutamine transport, determinate the cellular viability by annexin V/PI (Propidium Iodide) assay and manipulation of HL-60, NB-4 and KG-1 cells with conventional chemotherapy combined with inhibitors of glutaminolysis.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Supporting literature will be provided to the student and the laboratory tutor will be always available to discuss.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
No specific skills are expected. The student will be always under supervision.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students
- Fernandes Â; Azevedo MM; Pereira O; Sampaio-Marques B; Paiva A; Correia-Neves M; Castro; Ludovico P; Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches. doi: 10.18632/oncotarget.2947.
- Daniel J Klionsky;Kotb Abdelmohsen;Akihisa Abe;Md Joynal Abedin;Hagai Abeliovich;Abraham Acevedo Arozena; Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) doi: 10.1080/15548627.2015.1100356.
- Victor H Villar;Faten Merhi;Mojgan Djavaheri-Mergny; Raúl V Durán; Glutaminolysis and autophagy in cancer doi: 10.1080/15548627.2015.1053680.
- Jacque N; Ronchetti AM; Larrue C; Meunier G; Birsen R; Willems L; Saland E; Decroocq J; Maciel TT; Lambert M; Poulain L; Sujobert P; Joseph L; Chapuis N; Lacombe C; Moura IC; Demo S; Sarry JE; Recher C; Mayeux P; Tamburini J; Bouscary D; Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. doi: 10.1182/blood-2015-01-621870.
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