title: Neuroglobin, a pro-survival player in estrogen receptor α-positive cancer cells.
abstract: Recently, we reported that human neuroglobin (NGB) is a new player in the signal transduction pathways that lead to 17β-estradiol (E2)-induced neuron survival. Indeed, E2 induces in neuron mitochondria the enhancement of NGB level, which in turn impairs the activation of a pro-apoptotic cascade. Nowadays, the existence of a similar pathway activated by E2 in non-neuronal cells is completely unknown. Here, the role of E2-induced NGB upregulation in tumor cells is reported. E2 induced the upregulation of NGB in a dose- and time-dependent manner in MCF-7, HepG2, SK-N-BE, and HeLa cells transfected with estrogen receptor α (ERα), whereas E2 was unable to modulate the NGB expression in the ERα-devoid HeLa cells. Both transcriptional and extranuclear ERα signals were required for the E2-dependent upregulation of NGB in MCF-7 and HepG2 cell lines. E2 stimulation modified NGB intracellular localization, inducing a significant reduction of NGB in the nucleus with a parallel increase of NGB in the mitochondria in both HepG2 and MCF-7 cells. Remarkably, E2 pretreatment did not counteract the H2O2-induced caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, as well as Bcl-2 overexpression in MCF-7 and HepG2 cells in which NGB was stably silenced by using shRNA lentiviral particles, highlighting the pivotal role of NGB in E2-induced antiapoptotic pathways in cancer cells. Present results indicate that the E2-induced NGB upregulation in cancer cells could represent a defense mechanism of E2-related cancers rendering them insensitive to oxidative stress. As a whole, these data open new avenues to develop therapeutic strategies against E2-related cancers.
authors.affiliation: Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fiocchetti
authors.affiliation: Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Nuzzo
authors.affiliation: Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Totta
authors.affiliation: Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Acconcia
authors.affiliation: Interdepartmental Laboratory of Electron Microscopy, University Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ascenzi
authors.affiliation: Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marino
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000078787:Neuroglobin
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D004958:Estradiol; D005914:Globins