title: Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway.
abstract: Leukemia is a leading cause of cancer death. Recently, the latexin (Lxn) gene was identified as a potential tumor suppressor in several types of solid tumors and lymphoma, and Lxn expression was found to be absent or downregulated in leukemic cells. Whether Lxn functions as a tumor suppressor in leukemia and what molecular and cellular mechanisms are involved are unknown. In this study, the myeloid leukemogenic FDC-P1 cell line was used as a model system and Lxn was ectopically expressed in these cells. Using the protein pull-down assay and mass spectrometry, ribosomal protein subunit 3 (Rps3) was identified as a novel Lxn binding protein. Ectopic expression of Lxn inhibited FDC-P1 growth in vitro. More surprisingly, Lxn enhanced gamma irradiation-induced DNA damages and induced cell-cycle arrest and massive necrosis, leading to depletion of FDC-P1 cells. Mechanistically, Lxn inhibited the nuclear translocation of Rps3 upon radiation, resulting in abnormal mitotic spindle formation and chromosome instability. Rps3 knockdown increased the radiation sensitivity of FDC-P1, confirming that the mechanism of action of Lxn is mediated by Rps3 pathway. Moreover, Lxn enhanced the cytotoxicity of chemotherapeutic agent, VP-16, on FDC-P1 cells. Our study suggests that Lxn itself not only suppresses leukemic cell growth but also potentiates the cytotoxic effect of radio- and chemotherapy on cancer cells. Lxn could be a novel molecular target that improves the efficacy of anti-cancer therapy.
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: You
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wen
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pathak
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Gratuate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: D
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hauer-Jensen
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhou
authors.affiliation: 1] Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA [2] Gratuate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D063646:Carcinogenesis; D059447:Cell Cycle Checkpoints / Q000528:radiation effects*; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D043171:Chromosomal Instability / Q000528:radiation effects; D004249:DNA Damage; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D011836:Radiation Tolerance / Q000528:radiation effects; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D008941:Spindle Apparatus / Q000528:radiation effects; D013312:Stress, Physiological / Q000528:radiation effects
chemical_list: D000941:Antigens; C086812:Lxn protein, rat; D012269:Ribosomal Proteins; C429752:ribosomal protein 3