title: Extracellular Release of Annexin A2 is Enhanced upon Oxidative Stress Response via the p38 MAPK Pathway after Low-Dose X-Ray Irradiation.
abstract: The extracellular microenvironment affects cellular responses to various stressors including radiation. Annexin A2, which was initially identified as an intracellular molecule, is also released into the extracellular environment and is known to regulate diverse cell surface events, however, the molecular mechanisms underlying its release are not well known. In this study, we found that in cultured human cancer and non-cancerous cells an extracellular release of annexin A2 was greatly enhanced 1-4 h after a single 20 cGy X-ray dose, but not after exposure to ultraviolet C (UVC) radiation. Extracellular release of annexin A2 was also enhanced after H2O2 and nicotine treatments, which was suppressed by pretreatment with the antioxidant, N-acetyl cysteine. Among the oxidative stress pathway molecules examined in HeLa cells, AMP-activated protein kinase α (AMPKα) and p38 mitogen-activated protein kinase (MAPK) were mostly activated by low-dose X-ray radiation, and the p38 MAPK inhibitor, SB203580, but not compound C (an AMPKα inhibitor), suppressed the enhancement of the annexin A2 extracellular release after low-dose X irradiation. In addition, the enhancement was suppressed in the cells in which p38α MAPK was downregulated by siRNA. HeLa cells and human cultured cells preirradiated with 20 cGy or precultured in media from low-dose X-irradiated cells showed an increase in resistance to radiation-induced cell death, and the increase was suppressed by treatment of the irradiated cell-derived media with anti-annexin A2 antibodies. In addition, extracellularly added recombinant annexin A2 conferred cellular radiation resistance. These results indicate that an oxidative stress-activated pathway via p38 MAPK was involved in the extracellular release of annexin A2, and this pathway was stimulated by low-dose X-ray irradiation. Furthermore, released annexin A2 may function in low-dose ionizing radiation-induced responses, such as radioresistance.
authors.affiliation: a   Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuou-ku, Chiba 260-8670, Japan and.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kita
authors.affiliation: b   Department of Clinical Medicine, Faculty of Education, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Katsuo
authors.initials: K
authors.lastname: Sugita
authors.affiliation: a   Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuou-ku, Chiba 260-8670, Japan and.
authors.forename: Chihomi
authors.initials: C
authors.lastname: Sato
authors.affiliation: a   Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuou-ku, Chiba 260-8670, Japan and.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sugaya
authors.affiliation: a   Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuou-ku, Chiba 260-8670, Japan and.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sato
authors.affiliation: a   Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuou-ku, Chiba 260-8670, Japan and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017306:Annexin A2 / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects*; D014466:Ultraviolet Rays / Q000009:adverse effects; D014965:X-Rays / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017306:Annexin A2; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine