ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Fiocchetti, Marco; Camilli, Giulia; Acconcia, Filippo; Leone, Stefano; Ascenzi, Paolo; Marino, Maria

doi:10.1016/j.jsbmb.2015.02.005

Cited by 28 publications

(46 citation statements)

References 60 publications

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“…In conclusion, besides the role of NGB as an antioxidative agent , these results suggest that the E2‐induced NGB upregulation in cancer cells could represent a defense mechanism of E2‐related human breast cancer rendering them insensitive to several injury including chemotherapy. These novel findings could have important implications in the development of targeted therapeutics for overcoming paclitaxel insensitivity in human breast cancer.…”

Section: Resultsmentioning

confidence: 80%

“…This evidence prompted us to evaluate the involvement of NGB in the E2/ERα‐induced low sensitivity of MCF‐7 cells to paclitaxel‐induced apoptosis. Indeed, we recently demonstrated that NGB is an E2/ERα‐dependent compensatory protein, in which upregulation counteracts apoptosis induced by oxidative stress in several cancer cell lines . Data shown in Fig.…”

Section: Resultsmentioning

confidence: 82%

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Neuroglobin overexpression induced by the 17β-Estradiol-Estrogen receptor-α Pathway reduces the sensitivity of MCF-7 Breast cancer cell to paclitaxel

et al. 2016

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Although paclitaxel (Taxol) is an active chemotherapeutic agent for the treatment of breast cancer, not all breast tumors are sensitive to this drug. In particular, there is a wide agreement on the low sensitivity of estrogen receptor (ER) a-positive breast cancer to paclitaxel treatment. However, the ERa-based insensitivity to paclitaxel is still elusive. Here, the effect of the E2/ERa-dependent upregulation of neuroglobin (NGB), an antiapoptotic globin, on the reduced sensitivity of breast cancer cells to paclitaxelinduced apoptosis has been evaluated in ERa-containing MCF-7 cells. The E2 pretreatment enhances the ERa activity and significantly impairs paclitaxel-induced apoptosis as evaluated by Annexin V assay and PARP-1 cleavage. NGB displays a pivotal role in the E2/ERa-induced antiapoptotic pathway to abrogate paclitaxel-induced cell death in stable NGB-silenced MCF-7 cell clones. Moreover, in the absence of the active ERa, paclitaxel significantly reduces the NGB cell content. In conclusion, these results highlight the involvement of ERa activation and of E2/ERa-dependent NGB upregulation in the insensitivity of MCF-7 to paclitaxel. These novel findings could have important implications in the development of targeted therapeutics for overcoming paclitaxel insensitivity in ERa-positive human breast cancer. V C 2016 IUBMB Life, 68(8): [645][646][647][648][649][650][651] 2016

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 82%

Neuroglobin overexpression induced by the 17β-Estradiol-Estrogen receptor-α Pathway reduces the sensitivity of MCF-7 Breast cancer cell to paclitaxel

et al. 2016

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“…In addition, among the hypothesis put forward, several evidence support a role of this protein in different intracellular signaling pathways involved in the cell adaptive response to oxidative stress and/or hypoxia, ROS generation, ATP production, and apoptotic cascade . This intriguing vision of Ngb functions is supported by the Ngb low intracellular concentration and, its expression in cytosol, inner membrane of mitochondria and cell nucleus, and, particularly, by the broad spectrum of Ngb interacting proteins. Different conditions including hypoxia and oxidative stress challenge Ngb expression level/localization, and cell type specificity significantly affect Ngb interactions, adding obstacles to the full understanding of the globin interactome .…”

Section: Discussionmentioning

confidence: 98%

“…Therefore, even in the absence of any redox reaction between Ngb and cyt c , Ngb could abolish the apoptotic cascade . In addition, as demonstrated by co‐immunoprecipitation assays and confocal microscopy, Ngb, recruited to mitochondria, impacts on the apoptotic cascade by interacting with cyt c and impairs its release to cytosol …”

Section: Neuroglobin Interactors In Health and Diseasementioning

confidence: 99%

“…Nevertheless, it appears that basal levels of Ngb found in neurons have the ability to protect cells against a mild challenge, which can occur during normal cell function . On the other hand, during a high stress condition, such as strong oxidative stress, high levels of Ngb and its translocation into mitochondria are needed to prevent the apoptotic cascade . Even if Ngb is assumed to be a stress‐inducible protein, only 17β‐estradiol, a well‐known Ngb inducer, is able to increase both the whole cell concentration of Ngb and its level in the mitochondrial compartment to impair cell injury …”

Section: Neuroglobin Interactors In Health and Diseasementioning

confidence: 99%

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Neuroglobin and friends

Fiocchetti

Cipolletti

Brandi

et al. 2017

J of Molecular Recognition

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In the year 2000, the third member of the globin family was discovered in human and mouse brain and named neuroglobin (Ngb). Neuroglobin overexpression significantly protects both heart and brain from hypoxic/ischemic and oxidative stress-related insults, whereas decreased Ngb levels lead to an exacerbation of tissue injuries. Moreover, Ngb overexpression protects neurons from mitochondrial dysfunctions and neurodegenerative disorders such as Alzheimer disease; however, it facilitates the survival of cancer cells. Neuroglobin, representing a switch point for cell death and survival, has been reported to recognize a number of proteins involved in several metabolic pathways including ionic homeostasis maintenance, energy metabolism, mitochondrial function, and cell signaling. Here, the recognition properties of Ngb are reviewed to highlight its roles in health and disease.

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

Fiocchetti

Cipolletti

Ascenzi

et al. 2018

Journal Cellular Physiology

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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.

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ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Cited by 28 publications

References 60 publications

Neuroglobin overexpression induced by the 17β-Estradiol-Estrogen receptor-α Pathway reduces the sensitivity of MCF-7 Breast cancer cell to paclitaxel

Neuroglobin overexpression induced by the 17β-Estradiol-Estrogen receptor-α Pathway reduces the sensitivity of MCF-7 Breast cancer cell to paclitaxel

Neuroglobin and friends

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

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