Influence of Caloric Restriction on Constitutive Expression of NF-κB in an Experimental Mouse Astrocytoma

Abstract

BackgroundMany of the current standard therapies employed for the management of primary malignant brain cancers are largely viewed as palliative, ultimately because these conventional strategies have been shown, in many instances, to decrease patient quality of life while only offering a modest increase in the length of survival. We propose that caloric restriction (CR) is an alternative metabolic therapy for brain cancer management that will not only improve survival but also reduce the morbidity associated with disease. Although we have shown that CR manages tumor growth and improves survival through multiple molecular and biochemical mechanisms, little information is known about the role that CR plays in modulating inflammation in brain tumor tissue.Methodology/Principal FindingsPhosphorylation and activation of nuclear factor κB (NF-κB) results in the transactivation of many genes including those encoding cycloxygenase-2 (COX-2) and allograft inflammatory factor-1 (AIF-1), both of which are proteins that are primarily expressed by inflammatory and malignant cancer cells. COX-2 has been shown to enhance inflammation and promote tumor cell survival in both in vitro and in vivo studies. In the current report, we demonstrate that the p65 subunit of NF-κB was expressed constitutively in the CT-2A tumor compared with contra-lateral normal brain tissue, and we also show that CR reduces (i) the phosphorylation and degree of transcriptional activation of the NF-κB-dependent genes COX-2 and AIF-1 in tumor tissue, as well as (ii) the expression of proinflammatory markers lying downstream of NF-κB in the CT-2A malignant mouse astrocytoma, [e.g. macrophage inflammatory protein-2 (MIP-2)]. On the whole, our date indicate that the NF-κB inflammatory pathway is constitutively activated in the CT-2A astrocytoma and that CR targets this pathway and inflammation.ConclusionCR could be effective in reducing malignant brain tumor growth in part by inhibiting inflammation in the primary brain tumor.

Cancer as a Metabolic Disease: Implications for Novel Therapeutics

“…The metabolic shift from glucose metabolism to ketone body metabolism creates an anti-angiogenic, anti-inflammatory and proapoptotic environment within the tumor mass (192,(195)(196)(197)(198)(199). The general concept of a survival advantage of tumor cells over normal cells occurs when fermentable fuels are abundant, but not when they are limited (20).…”

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

“…CR and RKD will simultaneously target multiple metabolic pathways in tumor cells without causing adverse effects or toxicity to normal cells (Marsh et al, 2008a;Seyfried et al, 2010b;Shelton et al, 2010b;Zuccoli et al, 2010). The systemic energy transition from glucose to ketones will reduce inflammation in the tumor microenvironment, thus reducing progression as we recently described (Mulrooney et al, 2011).…”

“…We showed that calorie restriction; (a) reduces the phosphorylation and degree of transcriptional activation of the NF-B-dependent genes COX-2 and AIF-1 in CT-2A tumor tissue and, (b) reduces expression of pro-inflammatory markers lying downstream of NF-B, e.g., macrophage inflammatory protein-2 (MIP-2) (Mulrooney et al, 2011). On the whole, we showed that the NF-B inflammatory pathway is constitutively activated in the CT-2A astrocytoma and that CR targets this pathway and inflammation.…”

“…COX-2 enhances inflammation and promotes tumor cell survival (Portnow et al, 2002;Badie et al, 2003). We recently demonstrated that the p65 subunit of NF-B was expressed constitutively in the CT-2A astrocytoma compared with contra-lateral normal brain tissue (Mulrooney et al, 2011). NF-B also appears to activate mitochondrial glutaminase, which hydrolyzes glutamine to glutamate .…”

“…As long as brain cancer is viewed as something other than a disease of energy metabolism, the failures will likely continue in our opinion. In contrast to most current brain cancer therapies, CR and the RKD are the only therapeutic approaches that simultaneously target energy metabolism, angiogenesis, and inflammation through the IGF-1-PI3K-Akt-Hif-1a signaling (Mukherjee et al, 2002(Mukherjee et al, , 2004Marsh et al, 2008a;Seyfried et al, 2010b;Mulrooney et al, 2011). The therapeutic efficacy of the RKD can be enhanced especially when combined with drugs that further reduce availability of glucose and glutamine.…”