Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise. We found that glutamine deprivation inhibited leukemia cell growth but also led to a glucose-independent adaptation maintaining cell survival. A proteomic study revealed that glutamine withdrawal induced the upregulation of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT), two enzymes of the serine pathway. We further documented that both exogenous and endogenous serine were critical for leukemia cell growth and contributed to cell regrowth following glutamine deprivation. Increase in oxidative stress upon inhibition of glutamine metabolism was identified as the trigger of the upregulation of PHGDH. Finally, we showed that PHGDH silencing in vitro and the use of serine-free diet in vivo inhibited leukemia cell growth, an effect further increased when glutamine metabolism was blocked. In conclusion, this study identified serine as a key pro-survival actor that needs to be handled to sensitize leukemia cells to glutamine-targeting modalities.
Metastasis, the capacity of tumour cells to disseminate and grow at distant sites, is the main factor in cancer mortality. Compounds inhibiting migration and invasion of cancer cells are promising candidates for anticancer therapy strategies. We have generated nuclease-resistant RNA ligands (aptamers) recognizing highly metastatic cells with high affinity and specificity, and inhibiting their migratory and invasive potentials. Aptamers were generated by a cell-based subtractive SELEX technology using isogenic cell lines with similar tumorigenic potentials but opposite metastatic aggressiveness. Two aptamers, E37 and E10, bound specifically to the metastatically aggressive cell line and altered the phosphorylation of several tyrosine kinases. Fluorescent microscopy showed intracellular uptake of E37, in contrast to membrane binding of E10. Both aptamers inhibited migration of tumour cells in culture (50 and 85% inhibition with respect to control pool for E10 and E37, respectively) while only E10 inhibited cell invasion (275% with respect to control pool). This proof-of-concept study demonstrates the potential of cell-based SELEX to yield ligands that selectively recognize aggressive metastatic cells and inhibit phenotypes linked to metastatic potential.In cancer, a fatal issue is most often the consequence of metastatic spreading, but very few if any chemotherapies address the metastatic process itself. One reason may be that the process by which tumour cells metastasize is a still imperfectly understood succession of different molecular mechanisms. Another reason is that many of these molecular mechanisms pertain both to metastasis and to ubiquitous cellular activities. For instance, cell migration is an important and obligatory factor for the dissemination of tumour cells, as well as a general feature of many normal cells. Hence, it is far from trivial to target selectively the migration of cancer cells and not that of normal cells. Here, we explored new approaches to selectively target and inhibit specifically abnormal, context-irrelevant, cell migration with the aim to produce molecular binders for the recognition and, possibly, the control of metastatic activity.Among iterative selection methods based on Darwin's survival of the fittest, the SELEX (Systematic Evolution of Ligands by EXponential Enrichment) allows the in vitro evolution of small nucleic acid molecules (aptamers) recognizing a specific molecular target.1,2 Aptamers bind cognate targets with high affinity and specificity, assuming stable three-dimensional structures 3 and often perturb their function. 4 Recently, SELEX has been adapted to the recognition of undefined targets in complex environments, in particular in live cells.5 A high level of molecular discrimination can be obtained using subtractive SELEX protocols, where cells from homologous origin, one expressing the target or phenotype of interest and the other not expressing, are used to alternate negative and positive selection steps. Cellbased SELEX has shown its capacity to track ten...
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