Recently, we reported that human neuroglobin (NGB) is a new player in the signal transduction pathways that lead to 17ß-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 a (ERa), whereas E2 was unable to modulate the NGB expression in the ERa-devoid HeLa cells. Both transcriptional and extranuclear ERa 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.

Fiocchetti, M., Nuzzo, M.T., Totta, P., Acconcia, F., Ascenzi, P., Marino, M. (2014). Neuroglobin, a pro-survival player in estrogen receptor a-positive cancer cells. CELL DEATH & DISEASE, 5(10), e1449-e1449 [10.1038/cddis.2014.418].

Neuroglobin, a pro-survival player in estrogen receptor a-positive cancer cells

Fiocchetti, M.;Nuzzo, M. T.;Totta, P.;Acconcia, F.;Ascenzi, P.;Marino, M.
2014-01-01

Abstract

Recently, we reported that human neuroglobin (NGB) is a new player in the signal transduction pathways that lead to 17ß-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 a (ERa), whereas E2 was unable to modulate the NGB expression in the ERa-devoid HeLa cells. Both transcriptional and extranuclear ERa 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.
Fiocchetti, M., Nuzzo, M.T., Totta, P., Acconcia, F., Ascenzi, P., Marino, M. (2014). Neuroglobin, a pro-survival player in estrogen receptor a-positive cancer cells. CELL DEATH & DISEASE, 5(10), e1449-e1449 [10.1038/cddis.2014.418].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11590/327471
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