Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11
Menée à l'aide de lignées cellulaires et d'un modèle murin d'adénocarcinome canalaire du pancréas, cette étude met en évidence le rôle de l'autophagie dans la régulation du transporteur de la cystéine SLC7A11 et le métabolisme de cet acide aminé
Pancreatic cancer utilizes autophagy to survive stress and promote therapeutic resistance. However, the metabolic contribution of autophagy in PDAC has not been fully elucidated. We report that SLC7A11 function requires autophagy machinery for proper membrane localization in PDAC, allowing proper cystine transport. Our findings continue to support the use of autophagy inhibition as a therapeutic strategy in pancreatic cancer by demonstrating that this leads to inactivation of SLC7A11 and disruption of cysteine homeostasis. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is highly refractory to current therapies. We had previously shown that PDAC can utilize its high levels of basal autophagy to support its metabolism and maintain tumor growth. Consistent with the importance of autophagy in PDAC, autophagy inhibition significantly enhances response of PDAC patients to chemotherapy in two randomized clinical trials. However, the specific metabolite(s) that autophagy provides to support PDAC growth is not yet known. In this study, we demonstrate that under nutrient-replete conditions, loss of autophagy in PDAC leads to a relatively restricted impairment of amino acid pools, with cysteine levels showing a significant drop. Additionally, we made the striking discovery that autophagy is critical for the proper membrane localization of the cystine transporter SLC7A11. Mechanistically, autophagy impairment results in the loss of SLC7A11 on the plasma membrane and increases its localization at the lysosome in an mTORC2-dependent manner. Our results demonstrate a critical link between autophagy and cysteine metabolism and provide mechanistic insights into how targeting autophagy can cause metabolic dysregulation in PDAC. All study data are included in the article and/or supporting information.
Proceedings of the National Academy of Sciences , résumé, 2020