Original ContributionA noncanonical NF-κB pathway through the p50 subunit regulates Bcl-2 overexpression during an oxidative-conditioning hormesis response
Graphical abstract
Section snippets
Chemicals
All chemicals and reagents were of the highest analytical grade and most of them were purchased from Sigma (St. Louis, MO, USA). Reagents obtained from other suppliers are detailed in the text.
Cell culture
Mouse L929 lung fibroblasts were cultured at 37 °C in an atmosphere of 95% air and 5% CO2 as described elsewhere [37].
Cellular viability and oxidative-conditioning hormesis
L929 cells were seeded at 1×105 cells/well into 24-well plates (Corning, Acton, MA, USA) and were treated with 50 μM H2O2 for 9 h, to induce the OCH response, and it was compared in some
PI3K, Akt, and PKC regulate Bcl-2 expression during the hormetic response
Previously we reported the role played by Bcl-2 during the hormetic response induced by mild oxidative stress [36]. To determine the signaling mechanism that regulates Bcl-2 expression, here we evaluated the participation of the main kinases known for their contribution to cell survival against oxidative stress.
PI3K, Akt, and PKC-α phosphorylation was monitored at short time points after OCH treatment (50 µM H2O2) (Fig. 1). When PI3K and p-PI3K were evaluated, a fast activation was observed by
Discussion
In this work we have established two different signaling mechanisms that participate in the regulation of Bcl-2 expression during the hormetic response. The hormetic model or OCH was previously established in the L929 cell line [36], subjecting the cells to a mild oxidative stress (50 μM H2O2) for 9 h.
The first mechanism involves PI3K, Akt, NF-κB, and Bcl-2 and has been described before as part of the survival and antioxidant response against several toxic stimuli in various cell types [27], [39]
Acknowledgments
The authors thank Dr. A. Hernández from CINVESTAV for generously donating to us the actin antibody and M.Sc. R. Lazzarini and the CBS–UAMI Confocal Core for confocal images acquisition and analysis. This work was supported by CONACyT Grants CB-2006-1-59659 and CB-2012-1-178349 as well as the “Red Temática de Investigación en Salud y Desarrollo Social” from CONACyT and INGER: DI-PI004/2012.
References (72)
- et al.
Biological stress response terminology
Toxicol. Appl. Pharmacol.
(2007) Hormesis defined
Ageing Res. Rev.
(2008)- et al.
PI3K/Akt signaling pathway is required for neuroprotection of thalidomide on hypoxic–ischemic cortical neurons in vitro
Brain Res.
(2010) - et al.
Quercetin protects oligodendrocyte precursor cells from oxygen/glucose deprivation injury in vitro via the activation of the PI3K/Akt signaling pathway
Brain Res. Bull.
(2011) - et al.
Neuroprotective effects of neolignans isolated from Magnoliae Cortex against glutamate-induced apoptotic stimuli in HT22 cells
Food Chem. Toxicol.
(2013) - et al.
Ellagic acid prevents rat colon carcinogenesis induced by 1,2 dimethyl hydrazine through inhibition of AKT–phosphoinositide-3 kinase pathway
Eur. J. Pharmacol
(2011) - et al.
Bcl-2 family proteins as regulators of oxidative stress
Semin. Cancer Biol.
(2009) - et al.
Effect of overexpression of Bcl-2 on cellular oxidative damage, nitric oxide production, antioxidant defenses and the proteasome
Free Radic. Biol. Med.
(2001) - et al.
Königsberg, M. Bcl-2 protects against oxidative stress while inducing premature senescence
Free Radic. Biol. Med.
(2006) - et al.
Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K–Akt signaling pathway
FEBS Lett
(2009)
Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway
Toxicol. Appl. Pharmacol
PDCD6 additively cooperates with anti-cancer drugs through activation of NF-κB pathways
Cell. Signalling
Modulation of NF-κB activity by exchange of dimers
Mol. Cell
Königsberg, M. Bcl-2 sustains oxidative conditioning hormetic response by inducing Nrf-2 nuclear translocation
Free Radic. Biol. Med.
NF-kappaB activation but not PI3K/Akt is required for dexamethasone dependent protection against TNF-alpha cytotoxicity in L929 cells
FEBS Lett
Hepatocyte-specific c-Met deletion disrupts redox homeostasis and sensitizes to Fas-mediated apoptosis
J. Biol. Chem.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding
Anal. Biochem.
Protein kinase C-α: disease regulator and therapeutic target
Trends Pharmacol. Sci.
Protein kinase C signaling and oxidative stress
Free Radic. Biol. Med.
Nuclear factor-E2 (Nrf2) is regulated through the differential activation of ERK1/2 and PKC α/βII by Gymnasterkoreayne B
Cancer Lett.
PGD2 and PGE2 regulate gene expression of Prx 6 in primary macrophages via Nrf2
Free Radic. Biol. Med.
Immediate neuronal preconditioning by NS1619
Brain Res.
Hydrogen peroxide activates IkappaB kinases through phosphorylation of serine residues in the activation loops
FEBS Lett.
Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion
Am. J. Pathol.
4-Hydroxynonenal, a product of oxidative stress, leads to an antioxidant response in optic nerve head astrocytes
Exp. Eye Res.
NF-κB1 (p50) homodimers contribute to transcription of the bcl-2 oncogene
J. Biol. Chem.
NF-κB-inducible BCL-3 expression is an autoregulatory loop controlling nuclear p50/NF-κB1 residence
J. Biol. Chem.
Site-specific tyrosine phosphorylation of IkappaBalpha negatively regulates its inducible phosphorylation and degradation
J. Biol. Chem.
Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis
J. Biol. Chem.
A perspective on the scientific, philosophical, and policy dimensions of hormesis
Dose–Response
p27(Kip1) inhibits systemic autoimmunity through the control of Treg cell activity and differentiation
Arthritis Rheum.
Simultaneously targeting Bcl-2 and Akt pathways sensitizes nasopharyngeal carcinoma to tumor necrosis factor-related apoptosis-inducing ligand
Cancer Biother. Radiopharm.
Borneol alleviates oxidative stress via upregulation of Nrf2 and Bcl-2 in SH-SY5Y cells
Pharm. Biol.
α-Mangostin induces apoptosis in human chondrosarcoma cells through downregulation of ERK/JNK and Akt signaling pathway
Agric. Food Chem
Rapid reactive oxygen species (ROS) generation induced by curcumin leads to caspase-dependent and -independent apoptosis in L929 cells
Free Radic. Biol. Med.
Tea polyphenols induce apoptosis through mitochondrial pathway and by inhibiting nuclear factor-kappaB and Akt activation in human cervical cancer cells
Oncol. Res.
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