title: A Repertoire of MicroRNAs Regulates Cancer Cell Starvation by Targeting Phospholipase D in a Feedback Loop That Operates Maximally in Cancer Cells.
abstract: We report a negative feedback loop between the signaling protein phospholipase D (PLD), phosphatidic acid (PA), and a specific set of microRNAs (miRNAs) during nutrient starvation of breast cancer cells. We show that PLD expression is increased in four breast cancer cell lines and that hypoxia, cell overcrowding, and nutrient starvation for 3 to 6 h increase expression even further. However, after prolonged (>12-h) starvation, PLD levels return to basal or lower levels. The mechanism for this is as follows. First, during initial starvation, an elevated PA (the product of PLD enzymatic activity) activates mTOR and S6K, known to inhibit apoptosis, and enhances cell migration especially in post-epithelial-to-mesenchymal transition (post-EMT) cancer cells. Second, continued PA production in later starvation induces expression of PLD-targeting microRNA 203 (miR-203), miR-887, miR-3619-5p, and miR-182, which reduce PLD translation. We provide direct evidence for a feedback loop, whereby PLD induction upon starvation leads to PA, which induces expression of miRNAs, which in turn inhibits PLD2 translation. The physiological relevance for breast cancer cells is that as PA can activate cell invasion, then, due to the negative feedback, it can deprive mTOR and S6K of their natural activator. It can further prevent inhibition of apoptosis and allow cells to survive nutrient deprivation, which normal cells cannot do.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, Ohio, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Fite
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, Ohio, USA.
authors.forename: Lobna
authors.initials: L
authors.lastname: Elkhadragy
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, Ohio, USA julian.cambronero@wright.edu.
authors.forename: Julian
authors.identifier: http://orcid.org/0000-0002-7581-9227
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D012334:RNA, Neoplasm / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D010712:Phosphatidic Acids; D012334:RNA, Neoplasm; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D