Nuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

Bonini, Sara Anna; Ferrari-Toninelli, Giulia; Uberti, Daniela; Montinaro, Mery; Buizza, Laura; Lanni, Cristina; Grilli, Mariagrazia; Memo, Maurizio

doi:10.1523/jneurosci.1113-11.2011

Cited by 45 publications

(49 citation statements)

References 66 publications

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“…Furthermore, after treating MCF-7 and SKBR3 cells with SN50 35,36 (a highly selective inhibitor of NF-kB pathway) and/or PD98059 (an inhibitor of ERK), we observed the phosphorylation levels of IKKa/b, IkB and ERK decreased ( Fig. S1A and B).…”

Section: Let-7a Regulates Nf-kb and Mapk/erk Pathway In A Kras-dependmentioning

confidence: 93%

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

Xu¹,

Sun²,

Qin

et al. 2015

Cell Cycle

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Keywords: breast cancer stem cells, KRas, let-7a, mammosphere formation capacity, MAPK/ERK, NF-kB Abbreviations: BCSCs, breast cancer stem cells; MFE, mammosphere-forming efficiency Breast cancer stem cells (BCSCs) have the greatest potential to maintain tumorigenesis in all subtypes of tumor cells and were regarded as the key drivers of tumor. Recent evidence has demonstrated that BCSCs contributed to a high degree of resistance to therapy. However, how BCSCs self renewal and tumorigenicity are maintained remains obscure. Herein, our study illustrated that overexpression of let-7a reduced cell proliferation and mammosphere formation ability of breast cancer stem cells(BCSCs) in a KRas-dependent manner through different pathways in vitro and in vivo. To be specific, we provided the evidence that let-7a was decreased, and reversely the expression of KRas was increased with moderate expression in early stages (I/II) and high expression in advanced stages (III/IV) in breast cancer specimens. In addition, the negative correlation between let-7a and KRas was clearly observed. In vitro, we found that let-7a inhibited mammosphere-forming efficiency and the mammosphere-size via NF-kB and MAPK/ERK pathway, respectively. The inhibitory effect of let-7a on mammosphere formation efficiency and the size of mammospheres was abolished after the depletion of KRas. On the contrary, enforced expression of KRas rescued the effect of let-7a. In vivo, let-7a inhibited the growth of tumors, whereas the negative effect of let-7a was rescued after overexpressing KRas. Taken together, our findings suggested that let-7a played a tumor suppressive role in a KRas-dependent manner.

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Section: Let-7a Regulates Nf-kb and Mapk/erk Pathway In A Kras-dependmentioning

confidence: 93%

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

Xu¹,

Sun²,

Qin

et al. 2015

Cell Cycle

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“…), at 2-hour intervals. Twenty-four hours after the last BrdU dose, half of the mice (n 5 5 and 6 of vehicle-and tapentadol-treated mice, respectively) were transcardially perfused, and their brains were removed and prepared for immunohistochemical analysis as previously described (Bonini et al, 2011). The remaining mice were transcardially perfused 21 days after the last BrdU administration.…”

Section: Methodsmentioning

confidence: 99%

The Noradrenergic Component in Tapentadol Action Counteractsμ-Opioid Receptor–Mediated Adverse Effects on Adult Neurogenesis

et al. 2014

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Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining m-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of b2 and a2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing longterm use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.

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“…Surprisingly, no published studies have evaluated, in animal models, the antidepressant activity of ALC. The drug can act as a donor of acetyl groups to proteins (Pettegrew et al, 2000), including the p65 member of NF-kB transcription factors (Chiechio et al, 2006), which are implicated in adult neurogenesis and neuroplasticity (Denis-Donini et al, 2008;Koo et al, 2010;Bonini et al, 2011;Grilli and Meneghini, 2012). Interestingly, ALC modulates gene expression of metabotropic glutamate receptor 2 (mGlu2) via NF-kB p65 acetylation and this mechanism has been proposed for ALC-mediated analgesic effects (Chiechio et al, 2006(Chiechio et al, , 2009).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine

Cuccurazzu

Bortolotto

Valente

et al. 2013

Neuropsychopharmacol

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Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-kB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kB pathway, and in particular by p65 acetylation, and subsequent NF-kB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.

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Nuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

Cited by 45 publications

References 66 publications

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

The Noradrenergic Component in Tapentadol Action Counteractsμ-Opioid Receptor–Mediated Adverse Effects on Adult Neurogenesis

Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine

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