our previous research showing that supranutritional amounts of selenite induced apoptosis in CRC cells, we aimed to elucidate the underlying molecular mechanisms. Selenium, an essential metalloid trace element, is demonstrated to possess chemopreventive and chemotherapeutic effectiveness against numerous malignant cancers. 1,2 For example, epidemiologic and preclinical data demonstrate an inverse relationship between selenium intake and cancer risk ubiquitin conjugating in humans. 3,4 But, the particular underlying molecular mechanisms responsible for these anti-carcinogenic actions haven’t been fixed. Salt selenite, a standard kind of inorganic selenium, was recently noted to induce apoptosis in several cancer cell lines. 5?7 Our previous findings demonstrated that sodium selenite could specifically destroy colorectal cancer cells through the induction of apoptosis. 8,9 In today’s research, we further delineated the detailed mechanisms underlying seleniteinduced apoptosis. Forkhead box O transcription facets are very important regulators of diverse cellular activities, such as for instance proliferation, differentiation, protection against oxidative stress, apoptosis and autophagy. 10,11 These facets will also be associated with numerous diseases, including cancer. 12,13 The FoxO members of the family include four very related components FoxO1, FoxO3a, FoxO4 and FoxO614 Skin infection that may be posttranslationally controlled by numerous signaling molecules, which AKT acts as a significant upstream regulator. 15 AKT right phosphorylates FoxO household proteins and promotes their degradation. Subsequently, less FoxO protein accumulates in the nucleus to perform protranscriptional activities towards target genes involved with cell cycle arrest and apoptosis, such as puma, bim and p27. 16?18 PI3K/AKT signaling is shown to be frequently deregulated in several cancers, particularly in CRC. 19,20 Consequently, exploration of the effects of sodium selenite with this signaling pathway and MAPK inhibitors its involvement in apoptosis is of great importance for future clinical applications of selenium. In the current study, we found that selenite conferred its proapoptotic influence through modulation of the PI3K/AKT/ FOXO3a signaling link in a colon xenograft model and equally CRC cells. We provide clear evidence that sodium selenite inhibited the PI3K/AKT survival pathway in a reactive oxygen species dependent pathway. Furthermore, inhibition of AKT generated the activation of FoxO transcription factors and improved the expression of the target genes bim and PTEN, consequently, Bim was proven to increase seleniteinduced apoptosis, and PTEN zoomed the proapoptotic aftereffect of sodium selenite by inhibiting the AKT/FoxO3a/Bim signaling axis. Selenite induced apoptosis is associated with the Src/PI3K/AKT/FoxO3a signaling axis.