title: ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury.
abstract: Besides other mechanism(s) 17β-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor β (ERβ), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERβ level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERβ and HeLa cells transiently transfected with ERβ encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERβ-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100μM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERβ-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.
authors: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors: Marco
authors: M
authors: Fiocchetti
authors: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors: Giulia
authors: G
authors: Camilli
authors: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors: Filippo
authors: F
authors: Acconcia
authors: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors: Stefano
authors: S
authors: Leone
authors: Interdepartmental Laboratory of Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, I-00146 Roma, Italy.
authors: Paolo
authors: P
authors: Ascenzi
authors: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy. Electronic address: maria.marino@uniroma3.it.
authors: Maria
authors: M
authors: Marino
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005914:Globins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000078787:Neuroglobin; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
chemical_list: D047629:Estrogen Receptor beta; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D012333:RNA, Messenger; D004958:Estradiol; D005914:Globins; D045304:Cytochromes c
keywords: 17β-Estradiol; Apoptosis; Colon cancer cell line; Estrogen receptor β; Neuroglobin; Oxidative stress