Original Contribution A noncanonical NF-κB pathway through the p50 subunit regulates Bcl-2 overexpression during an oxidative-conditioning hormesis response Armando Luna-López a , Viridiana Y. González-Puertos b , Jacqueline Romero-Ontiveros b , José L. Ventura-Gallegos c , Alejandro Zentella c , Luis E. Gomez-Quiroz b , Mina Königsberg b,n a Instituto Nacional de Geriatría, SSA, México, DF 10200, México b Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Iztapalapa, México, DF 09340, México c Departamento de Medicina Genómica y Toxicología Ambiental, IIB, Universidad Nacional Autonoma de Mexico, and Departamento de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” México, DF, México article info Article history: Received 4 December 2012 Received in revised form 27 March 2013 Accepted 25 April 2013 Available online 3 May 2013 Keywords: Adaptive response Hormesis Oxidative stress NF-κB Akt PI3K PKC Bcl-2 Hydrogen peroxide Free radicals abstract Cells can respond to damage and stress by activating various repair and survival pathways. One of these responses can be induced by preconditioning the cells with sublethal stress to provoke a prosurvival response that will prevent damage and death, and which is known as hormesis. Bcl-2, an antiapoptotic protein recognized by its antioxidant and prosurvival functions, has been documented to play an important role during oxidative-conditioning hormesis. Using an oxidative-hormetic model, which was previously established in the L929 cell line by subjecting the cells to a mild oxidative stress of 50 μM H 2 O 2 for 9 h, we identified two different transductional mechanisms that participate in the regulation of Bcl-2 expression during the hormetic response. These mechanisms converge in activating the nuclear transcription factor NF-κB. Interestingly, the noncanonical p50 subunit of the NF-κB family is apparently the subunit that participates during the oxidative-hormetic response. & 2013 Elsevier Inc. All rights reserved. Mammalian cells can respond to damage and stress by activating various repair and survival pathways. Preconditioning the cells to sublethal stress is known to induce a prosurvival response that prevents damage and death. Hence, as a consensus terminology to unify the main mechanism that preconditioning and adaptive responses have in common, the term hormesis has been proposed, suggesting that exposure to low levels of stress will activate existing cellular and molecular pathways that will enhance the ability of the cell and organism to withstand more severe stress [1–3]. Every year many papers are published describing very different molecules that protect cells against oxidative insults, hypoxic– ischemic damage [4], oxygen and glucose deprivation [5], xeno- biotic toxicity, etc. Most of the molecules analyzed improve cellular survival by increasing Bcl-2 expression [6,7]. There are also reports in which preexposure to sublethal stress creates an antiapoptotic environment that prevents cell death. This precon- ditioning treatment generates tolerance or adaptation to oxidative stress by induction of the overexpression of survival genes such as Bcl-2 [8,9]. Interestingly, studies with transformed cells have shown that molecules that inhibit NF-κB and the Akt/phosphati- dylinositol 3-kinase (PI3K) pathway, such as xanthone derivates, α-mangostin [10], curcumin [11], green tea polyphenols [12], ellagic acid (a common component of berries) [13], fucoidan (a sulfated polysaccharide) [14], osthole [15], and bromelain (obtained from pineapple) [16], are reported to have therapeutic applications in the treatment of cancer because they eliminate cellular defense mechanisms, decrease Bcl-2 levels, and induce cell death. Bcl-2 has been recognized for its cytoprotective, antioxidant, and antiapoptotic functions [17–19]. Bcl-2 is also known to increase reduced glutathione levels [20] and superoxide dismutase and proteasome activity [21]. In addition to its protective activity, Bcl-2 has been demonstrated to have a cell cycle inhibitory function by retarding mammalian cell proliferation [22] and by its ability to induce cellular senescence [23]. Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed Free Radical Biology and Medicine 0891-5849/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.freeradbiomed.2013.04.033 n Corresponding author. Fax: +5255 5804 4727. E-mail address: mkf@xanum.uam.mx (M. Königsberg). Free Radical Biology and Medicine 63 (2013) 41–50