Extracellular NAMPT/Visfatin induces proliferation through ERK1/2 and AKT and inhibits apoptosis in breast cancer cells

Gholinejad, Zafar; Kheiripour, Nejat; Nourbakhsh, Mitra; Ilbeigi, Davod; Behroozfar, Kiarash; Hesari, Zahra; Golestani, Abolfazl; Shabani, Mohammad; Einollahi, Nahid

doi:10.1016/j.peptides.2017.04.007

Cited by 65 publications

(55 citation statements)

References 50 publications

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“…Considering the importance of p53 as a substrate for SIRT1 and induction of SIRT1 by visfatin, in this study p53 acetylation status was investigated and found to be decreased by visfatin. We had previously reported protective and antiapoptotic effects of visfatin in MCF‐7 cells . It has also been shown that visfatin increases the viability of pancreatic β‐cells .…”

Section: Discussionmentioning

confidence: 91%

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Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells

Behrouzfar

Alaee

Nourbakhsh

et al. 2017

Cell Biochemistry & Function

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Visfatin, which is secreted as an adipokine and cytokine, has been implicated in cancer development and progression. In this study, we investigated the NAD-producing ability of visfatin and its relationship with SIRT1 (silent information regulator 2) and p53 to clarify the role of visfatin in breast cancer. MCF-7 breast cancer cells were cultured and treated with visfatin. SIRT1 activity was assessed by measuring fluorescence intensity from fluoro-substrate peptide. To investigate the effect of visfatin on p53 acetylation, SDS-PAGE followed by western blotting was performed using specific antibodies against p53 and its acetylated form. Total NAD was measured both in cell lysate and the extracellular medium by colorimetric method. Visfatin increased both extracellular and intracellular NAD concentrations. It also induced proliferation of breast cancer cells, an effect that was abolished by inhibition of its enzymatic activity. Visfatin significantly increased SIRT1 activity, accompanied by induction of p53 deacetylation. In conclusion, the results show that extracellular visfatin produces NAD that causes upregulation of SIRT1 activity and p53 deacetylation. These findings explain the relationship between visfatin and breast cancer progression.

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Section: Discussionmentioning

confidence: 91%

“…Studies on colorectal and prostate cancer cells have shown similar results . Visfatin exerts proliferative effect on MCF‐7 cancer cells, and activation of several signalling pathways have been suggested for this adipokine …”

Section: Discussionmentioning

confidence: 99%

Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells

Behrouzfar

Alaee

Nourbakhsh

et al. 2017

Cell Biochemistry & Function

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“…For example, NAMPT overexpression in breast cancer cells and extracellular NAMPT (eNAMPT) released by melanoma cell have both been associated with AKT phosphorylation (118,119). Exogenous eNAMPT was also found to induce phosphorylation of AKT and ERK1/2 and increase proliferation of breast cancer cells, and the use of AKT and ERK1/2 inhibitors could abrogate these effects (120). In multiple cancer models, a decrease in phospho-ERK1/2 was observed with NAMPT inhibition (44, 121, 122) and combining NAMPT inhibitors with ERK1/2 blockade enhanced cell death (121).…”

Section: Oncogenic Signalingmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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“…Indeed, it has been postulated that NAMPT may participate in the regulation of inflammation and is responsible for many inflammatory diseases 6,7 . NAMPT was also involved in the regulation of apoptosis 8‐10 . FK866 is an inhibitor of NAMPT 11‐13 .…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

Tan

Chen

Ren

et al. 2020

Ann Clin Transl Neurol

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Objective: FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which exhibits neuroprotective effects in ischemic brain injury. However, in traumatic brain injury (TBI), the role and mechanism of FK866 remain unclear. The present research was aimed to investigate whether FK866 could attenuate TBI and clarified the underlying mechanisms. Methods: A controlled cortical impact model was established, and FK866 at a dose of 5 mg/kg was administered intraperitoneally at 1 h and 6 h, then twice per day post-TBI until sacrifice. Brain water content, Evans blue dye extravasation, modified neurological severity scores (mNSS), Morris water maze test, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blot were performed. Results: The results demonstrated that FK866 significantly mitigated the brain edema, blood-brain barrier (BBB) disruption, and ameliorated the neurological function post-TBI. Moreover, FK866 decreased the number of Iba-1-positive cells, GFAP-positive astrocytes, and AQP4-positive cells. FK866 reduced the protein levels of proinflammatory cytokines and inhibited NF-jB from translocation to the nucleus. FK866 upregulated the expression of Bcl-2, diminished the expression of Bax and caspase 3, and the number of apoptotic cells. Moreover, p38 MAPK and ERK activation were significantly inhibited by FK866. Interpretation: FK866 attenuated TBI-induced neuroinflammation and apoptosis, at least in part, through p38/ERK MAPKs signaling pathway. 742

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Extracellular NAMPT/Visfatin induces proliferation through ERK1/2 and AKT and inhibits apoptosis in breast cancer cells

Cited by 65 publications

References 50 publications

Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells

Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

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