title: Hypoxia Induces Autophagy through Translational Up-Regulation of Lysosomal Proteins in Human Colon Cancer Cells.
abstract: Hypoxia occurs in a wide variety of physiological and pathological conditions, including tumorigenesis. Tumor cells have to adapt to hypoxia by altering their gene expression and protein synthesis. Here, we showed that hypoxia inhibits translation through activation of PERK and inactivation of mTOR in human colon cancer HCT116 cells. Prolonged hypoxia (1% O2, 16 h) dramatically inhibits general translation in HCT116 cells, yet selected mRNAs remain efficiently translated under such a condition. Using microarray analysis of polysome- associated mRNAs, we identified a large number of hypoxia-regulated genes at the translational level. Efficiently translated mRNAs during hypoxia were validated by polysome profiling and quantitative real-time RT-PCR. Pathway enrichment analysis showed that many of the up-regulated genes are involved in lysosome, glycan and lipid metabolism, antigen presentation, cell adhesion, and remodeling of the extracellular matrix and cytoskeleton. The majority of down-regulated genes are involved in apoptosis, ubiquitin-mediated proteolysis, and oxidative phosphorylation. Further investigation showed that hypoxia induces lysosomal autophagy and mitochondrial dysfunction through translational regulation in HCT116 cells. The abundance of several translation factors and the mTOR kinase activity are involved in hypoxia-induced mitochondrial autophagy in HCT116 cells. Our studies highlight the importance of translational regulation for tumor cell adaptation to hypoxia.
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.|Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Lai
authors.affiliation: Bioinformatics Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiao-May
authors.initials: CM
authors.lastname: Chang
authors.affiliation: Bioinformatics Center, National Cheng Kung University, Tainan, Taiwan.|Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: H Sunny
authors.initials: HS
authors.lastname: Sun
mesh_terms: D001343:Autophagy / Q000235:genetics*; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D008247:Lysosomes / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C546842:MTOR protein, human; C460640:EIF2AK3 protein, human; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase