title: The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells.
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.
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France; Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Michaël
authors.initials: M
authors.lastname: Boyer-Guittaut
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Poillet
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bôle-Richard
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA; Department of Veterans Affairs; Birmingham VA Medical Center; Birmingham, AL USA.
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Benavides
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Fatima-Zahra
authors.initials: FZ
authors.lastname: Chakrama
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Fraichard
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Despouy
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Jouvenot
authors.affiliation: Université de Franche-Comté; Laboratoire de Biochimie; EA3922 Estrogènes; Expression Génique et Pathologies du Système Nerveux Central; Sciences et Techniques; Besançon, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Delage-Mourroux
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA; Center for Free Radical Biology; University of Alabama at Birmingham; Birmingham, AL USA; Department of Veterans Affairs; Birmingham VA Medical Center; Birmingham, AL USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071456:Sequestosome-1 Protein; D014410:Tumor Stem Cell Assay; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004272:DNA, Mitochondrial; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C491997:BECN1 protein, human; C430503:GABARAPL1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C099718:SQSTM1 protein, human; C027576:4-hydroxy-2-nonenal
keywords: GABARAP; GABARAPL1; GEC1; LAMP1; LC3; MDA-MB-436; autophagy; breast cancer; lysosome; mitochondria; mitophagy