The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells |
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Authors: | Micha?l Boyer-Guittaut Laura Poillet Qiuli Liang Elodie B?le-Richard Xiaosen Ouyang Gloria A Benavides Fatima-Zahra Chakrama Annick Fraichard Victor M Darley-Usmar Gilles Despouy Michèle Jouvenot Régis Delage-Mourroux Jianhua Zhang |
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Affiliation: | 1.Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France;2.Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA;3.Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA;4.Department of Veterans Affairs; Birmingham VA Medical Center; Birmingham, AL USA |
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Abstract: | GABARAPL1/GEC1 is an early estrogen-induced gene which encodes a protein highly conserved from C. elegans to humans. Overexpressed GABARAPL1 interacts with GABAA or kappa opioid receptors, associates with autophagic vesicles, and inhibits breast cancer cell proliferation. However, the function of endogenous GABARAPL1 has not been extensively studied. We hypothesized that GABARAPL1 is required for maintaining normal autophagic flux, and plays an important role in regulating cellular bioenergetics and metabolism. To test this hypothesis, we knocked down GABARAPL1 expression in the breast cancer MDA-MB-436 cell line by shRNA. Decreased expression of GABARAPL1 activated procancer responses of the MDA-MB-436 cells including increased proliferation, colony formation, and invasion. In addition, cells with decreased expression of GABARAPL1 exhibited attenuated autophagic flux and a decreased number of lysosomes. Moreover, decreased GABARAPL1 expression led to cellular bioenergetic changes including increased basal oxygen consumption rate, increased intracellular ATP, increased total glutathione, and an accumulation of damaged mitochondria. Taken together, our results demonstrate that GABARAPL1 plays an important role in cell proliferation, invasion, and autophagic flux, as well as in mitochondrial homeostasis and cellular metabolic programs. |
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Keywords: | autophagy breast cancer GABARAP GABARAPL1 GEC1 LAMP1 LC3 lysosome MDA-MB-436 mitochondria mitophagy |
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