Astaxanthin inhibits NF-κB and Wnt/β-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer

Background: The oncogenic transcription factors NF-kappa B and beta-catenin, constitutively activated by upstream serine/threonine kinases control several cellular processes implicated in malignant transformation including apoptosis evasion. The aim of this study was to investigate the chemopreventive effects of astaxanthin, an antioxidant carotenoid, in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to modulate NF-kappa B and Wnt signaling pathways and induce apoptosis. Methods: We determined the effect of dietary supplementation of astaxanthin on the oncogenic signaling pathways - NF-kappa B and Wnt/beta-catenin, their upstream activator kinases - Erk/MAPK and PI-3K/Akt, and the downstream event - apoptosis evasion by real-time quantitative RT-PCR, western blot, and immunohistochemical analyses. Results: We found that astaxanthin inhibits NF-kappa B and Wnt signaling by downregulating the key regulatory enzymes IKK beta and GSK-3 beta. Analysis of gene expression and docking interactions revealed that inhibition of these pathways may be mediated via inactivation of the upstream signaling kinases Erk/Akt by astaxanthin. Astaxanthin also induced caspase-mediated mitochondrial apoptosis by downregulating the expression of antiapoptotic Bcl-2, p-Bad, and survivin and upregulating proapoptotic Bax and Bad, accompanied by efflux of Smac/Diablo and cytochrome-c into the cytosol, and induced cleavage of poly (ADP-ribose) polymerase (PARP). Conclusions: The results provide compelling evidence that astaxanthin exerts chemopreventive effects by concurrently inhibiting phosphorylation of transcription factors and signaling kinases and inducing intrinsic apoptosis. General significance: Astaxanthin targets key molecules in oncogenic signaling pathways and induces apoptosis and is a promising candidate agent for cancer prevention and therapy. (c) 2013 Elsevier B.V. All rights reserved.