PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells

H Luo,C Xu,J Duan,Y Yang,P Wu,Q Jiang

doi:10.1038/cddis.2013.3

Abstract

Mounting evidence shows that selenium possesses chemotherapeutic potential against tumor cells, including leukemia, prostate cancer and colorectal cancer (CRC) cells. However, the detailed mechanism by which sodium selenite specifically kills tumor cells remains unclear. Herein, we demonstrated that supranutritional doses of selenite-induced apoptosis in CRC cells through reactive oxygen species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signaling pathway. First, we found that selenite treatment in HCT116 and SW480 CRC cells caused inhibition of AKT and the nuclear accumulation of FoxO3a by western blot and immunofluorescence analyses, respectively, thereby facilitating transcription of the target genes bim and PTEN. Modulation of the AKT/FoxO3a/Bim signaling pathway by chemical inhibitors or RNA interference revealed that these events were critical for selenite-induced apoptosis in CRC cells. Additionally, we discovered that FoxO3a-mediated upregulation of PTEN exerted a further inhibitory effect on the AKT survival pathway. We also corroborated our findings in vivo by performing immunohistochemistry experiments. In summary, our results show that selenite could induce ROS-dependent FoxO3a-mediated apoptosis in CRC cells and xenograft tumors through PTEN-mediated inhibition of the PI3K/AKT survival axis. These results help to elucidate the molecular mechanisms underlying selenite-induced cell death in tumor cells and provide a theoretical basis for translational applications of selenium.

Highlights

Forkhead box O (FoxO) transcription factors are crucial regulators of diverse cellular activities, such as proliferation, differentiation, defense against oxidative stress, apoptosis and autophagy.[10,11] These factors are associated with multiple diseases, including cancer.[12,13] The FoxO family members include four highly related factors—FoxO1, FoxO3a, FoxO4 and FoxO614—that can be posttranslationally regulated by various signaling molecules, of which AKT acts as an important upstream regulator.[15]
These results indicated that selenite inhibited Src/PI3K/PDK1/AKT signaling and activated FoxO family proteins in HCT116 and SW480 colorectal cancer (CRC) cells
The present study presents evidence that the AKT/FoxO3a/ Bim/PTEN signaling axis is closely associated with seleniteinduced apoptosis in CRC cells and xenograft tumors

Summary

Introduction

Forkhead box O (FoxO) transcription factors are crucial regulators of diverse cellular activities, such as proliferation, differentiation, defense against oxidative stress, apoptosis and autophagy.[10,11] These factors are associated with multiple diseases, including cancer.[12,13] The FoxO family members include four highly related factors—FoxO1, FoxO3a, FoxO4 and FoxO614—that can be posttranslationally regulated by various signaling molecules, of which AKT acts as an important upstream regulator.[15]. Less FoxO protein accumulates in the nucleus to execute protranscriptional actions towards target genes involved in cell-cycle arrest and apoptosis, such as bim, puma and p27.16–18 PI3K/AKT signaling has been shown to be frequently deregulated in various cancers, in CRC.[19,20] exploration of the effects of sodium selenite on this signaling pathway and its involvement in apoptosis is of great significance for future clinical applications of selenium. Inhibition of AKT led to the activation of FoxO transcription factors and enhanced the expression of the target genes bim and PTEN; as a result, Bim was shown to promote seleniteinduced apoptosis, and PTEN amplified the proapoptotic effect of sodium selenite by inhibiting the AKT/FoxO3a/Bim signaling axis

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