Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells
2017
Mesclon, Florent | Lambert-Langlais, Sarah | Carraro, Valerie | Parry, Laurent | Hainault, Isabelle | Jousse, Céline | Maurin, Anne-Catherine | Bruhat, Alain | Fafournoux, Pierre | Averous, Julien | Unité de Nutrition Humaine (UNH) ; Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]) | Service Biochimie et Génétique Moléculaire [CHU Clermont-Ferrand] ; CHU Gabriel Montpied [Clermont-Ferrand] ; CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand] ; CHU Clermont-Ferrand-Pôle Biologie médicale et Anatomie pathologique [CHU Clermont-Ferrand] ; CHU Gabriel Montpied [Clermont-Ferrand] ; CHU Clermont-Ferrand-CHU Clermont-Ferrand | Centre de Recherche des Cordeliers (CRC) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Université Paris Descartes - Paris 5 (UPD5) | Institut National de la Santé et de la Recherche Médicale (INSERM) | Université Pierre et Marie Curie - Paris 6 (UPMC) | Institut National de la Recherche Agronomique (INRA);Fondation ARC pour la Recherche sur le Cancer;Auvergne-Rhone-Alpes
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 eiF2alpha/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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