Date Published: November 8, 2011
Publisher: Impact Journals LLC
Author(s): Lan Xiang, Yukiko Nakamura, Young-Mi Lim, Yasutoyo Yamasaki, Yumi Kurokawa-Nose, Wakako Maruyama, Toshihiko Osawa, Akira Matsuura, Noboru Motoyama, Leo Tsuda.
The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.
The insulin/IGF-1 signaling pathway regulates aging processes in Drosophila melanogaster, Caenorhabditis elegans, and mammals [1, 2]. Phosphoinositide-3-kinase (PI3K) and Akt kinase are critical downstream components of the insulin/IGF-1 pathway, and regulate the transcriptional activity of O-type forkhead domain transcription factors (FOXOs) . There is a large family of mammalian FOXO transcription factors, which includes FOXO1, FOXO3, FOXO4, and FOXO6 [3, 4]. These proteins are involved in many cellular events, such as cell cycle arrest, apoptosis, DNA repair, glucose metabolism, anti-oxidative stress response, and longevity [5-7].
We present here the first evidence that the small chemical compound THC is associated with the anti-oxidative stress response and extension of life span via the FOXO transcription factor. Using a mammalian cell culture system, we found that THC regulated FOXO4 nuclear translocation (Figure 1). Akt may be involved in this effect, since THC treatment caused Akt dephosphorylation. Phospho-Akt normally prevents the nuclear localization of FOXO (Figure 3). To support this analysis, we found that THC extended the life span of Drosophila under oxidative stress conditions and that this effect was foxo-dependent (Figure 4). Furthermore, THC extended the life span of Drosophila under normal conditions, and this extension required foxo and d4E-BP activity (Figure 6). These findings support the idea that oxidative stress may correlate with life-span extension. Notably, the effect of THC on life span also seemed to depend on Sir2 activity (Figure 7), suggesting that THC regulates aging processes via an evolutionally conserved regulatory network of genes that includes both foxo and Sir2.