Dissecting the 17β-estradiol pathways necessary for neuroglobin anti-apoptotic activity in breast cancer.
Marco FiocchettiManuela CipollettiPaolo AscenziMaria MarinoPublished in: Journal of cellular physiology (2018)
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.
Keyphrases
- breast cancer cells
- cell death
- oxidative stress
- protein kinase
- signaling pathway
- reactive oxygen species
- diabetic rats
- binding protein
- anti inflammatory
- protein protein
- cell proliferation
- dna damage
- induced apoptosis
- poor prognosis
- amino acid
- papillary thyroid
- spinal cord
- estrogen receptor
- squamous cell carcinoma
- ischemia reperfusion injury
- endothelial cells
- young adults
- epithelial mesenchymal transition
- drug induced
- pi k akt
- small molecule
- endoplasmic reticulum
- cancer therapy
- tyrosine kinase
- heat shock
- endoplasmic reticulum stress