Dissecting the 17β-estradiol pathways necessary for neuroglobin anti-apoptotic activity in breast cancer

Neuroglobin (NGB) is a relatively recent discovered monomeric heme-protein, which behave in neurons as a sensor of injuring stimuli including oxidative stress, hypoxia, and neurotoxicity. In addition, the anti-apoptotic activity of overexpressed NGB has been reported both in neurons and in Cancer cell lines. We recently demonstrated that, NGB functions as a compensatory protein of the steroid hormone 17β-estradiol (E2) protecting Cancer cells against the apoptotic death induced by oxidative stress. However, the E2-induced signaling pathways at the root of NGB over-expression and mitochondrial re-localization in breast Cancer cells is still elusive. By using a kinase screening library, here, we report that: i) There is a strong positive correlation between NGB and ERα expression and activity in breast Cancer cells; ii) The E2-activated phosphatidyl-inositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) pathways are necessary to modulate the NGB protein levels; iii) The E2-induced persistent activation of Akt drive NGB to mitochondria; iv) Reactive Oxygen Species (ROS)-inducing compounds activating rapidly and transiently Akt does not affect the NGB mitochondrial level; and v) High level of NGB into mitochondria are necessary for the pro-survival and anti-apoptotic effect of this globin in Cancer cells. As a whole, these results underline the E2 triggered pathways in E2-responsive breast Cancer cells that involve NGB as a compensatory protein devoted to Cancer cell survival.

breast cancer cells; estrogen; estrogen receptor alpha; neuroglobin; signal pathways.