title: Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment.
abstract: Lipogenesis inhibition was reported to induce apoptosis and repress proliferation of cancer cells while barely affecting normal cells. Lipins exhibit dual function as enzymes catalyzing the dephosphorylation of phosphatidic acid to diacylglycerol and as co-transcriptional regulators. Thus, they are able to regulate lipid homeostasis at several nodal points. Here, we show that lipin-1 is up-regulated in several cancer cell lines and overexpressed in 50 % of high grade prostate cancers. The proliferation of prostate and breast cancer cells, but not of non-tumorigenic cells, was repressed upon lipin-1 knock-down. Lipin-1 depletion also decreased cancer cell migration through RhoA activation. Lipin-1 silencing did not significantly affect global lipid synthesis but enhanced the cellular concentration of phosphatidic acid. In parallel, autophagy was induced while AKT and ribosomal protein S6 phosphorylation were repressed. We also observed a compensatory regulation between lipin-1 and lipin-2 and demonstrated that their co-silencing aggravates the phenotype induced by lipin-1 silencing alone. Most interestingly, lipin-1 depletion or lipins inhibition with propranolol sensitized cancer cells to rapamycin. These data indicate that lipin-1 controls main cellular processes involved in cancer progression and that its targeting, alone or in combination with other treatments, could open new avenues in anticancer therapy.
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Tour de Pathologie, Sart-Tilman, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Brohée
authors.affiliation: Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), Namur, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demine
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Tour de Pathologie, Sart-Tilman, Belgium.
authors.forename: Jérome
authors.initials: J
authors.lastname: Willems
authors.affiliation: Laboratory of Biochemistry and Cell Biology (URBC), NARILIS (Namur Research Institute for Life Sciences), University of Namur (UNamur), Namur, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Arnould
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Tour de Pathologie, Sart-Tilman, Belgium.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Colige
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Tour de Pathologie, Sart-Tilman, Belgium.
authors.forename: Christophe F
authors.initials: CF
authors.lastname: Deroanne
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D050155:Lipogenesis; D008297:Male; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011433:Propranolol / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C502575:LPIN2 protein, human; D009687:Nuclear Proteins; D038601:Ribosomal Protein S6; C066737:RHOA protein, human; D011433:Propranolol; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase; D020742:rhoA GTP-Binding Protein; D020123:Sirolimus
keywords: RhoA; lipin-1; metabolism; prostate cancer; rapamycin
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