Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells
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Florent Mesclon1, Sarah Lambert-Langlais2, Valérie Carraro1, Laurent Parry1, Isabelle Hainault3, Céline Jousse1, Anne-Catherine Maurin1, Alain Bruhat1, Pierre Fafournoux1, Julien Averous1
1Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France
2Department of Medical Biochemistry and Molecular Biology, CHU de Clermont-Ferrand, 63003 Clermont-Ferrand Cedex 1, France
3Institute of Cardiometabolism and Nutrition, Université Pierre et Marie Curie, INSERM, UMR S1138, Centre de Recherche des Cordeliers, 75006 Paris, France
Julien Averous, email: [email protected]
Pierre Fafournoux, email: [email protected]
Keywords: ATF4, amino acids, apoptosis, cancer, resistance
Received: July 22, 2016 Accepted: February 12, 2017 Published: March 02, 2017
The uncontrolled growth of tumor can lead to the formation of area deprived in nutrients. Due to their high genetic instability, tumor cells can adapt and develop resistance to this pro-apoptotic environment. Among the resistance mechanisms, those involved in the resistance to long-term amino acid restriction are not elucidated. A long-term amino acid restriction is particularly deleterious since nine of them cannot be synthetized by the cells. In order to determine how cancer cells face a long-term amino acid deprivation, we developed a cell model selected for its capacity to resist a long-term amino acid limitation. We exerted a selection pressure on mouse embryonic fibroblast to isolate clones able to survive with low amino acid concentration. The study of several clones revealed an alteration of the eiF2α/ATF4 pathway. Compared to the parental cells, the clones exhibited a decreased expression of the transcription factor ATF4 and its target genes. Likewise, the knock-down of ATF4 in parental cells renders them resistant to amino acid deprivation. Moreover, this association between a low level of ATF4 protein and the resistance to amino acid deprivation was also observed in the cancer cell line BxPC-3. This resistance was abolished when ATF4 was overexpressed. Therefore, decreasing ATF4 expression may be one important mechanism for cancer cells to survive under prolonged amino acid deprivation.
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