Abstract
Survivin-2B, a known splice variant of survivin, has been reported to promote cell death in some cancer cells, although it keeps prosurvival function in others, and the mechanisms are unclear. In this report, we discovered that selenite, an antitumor agent, switched protective autophagy to apoptosis in NB4 cells. In this process, the level of survivin-2B was decreased and the interaction between IKK alpha and survivin-2B in the nucleus was attenuated, which further led to the decrease of nuclear IKK alpha. As a result, P73, a known transcript factor of UVRAG, was downregulated. Therefore, the expression of UVRAG, one of the initiators of autophagy, was inhibited. The regulatory status of survivin-2B was also proved in NB4 cells after different chemicals' exposure and in other tumor cell lines (Jurkat, HCT116). Finally, experiments in vivo confirmed that the alterations of survivin-2B, IKK alpha, P73 and UVRAG were the same as that in vitro. Taken together, survivin-2B promoted autophagy and further regulated cell death by accumulating and stabilizing IKK alpha in the nucleus.
Highlights
Selenium is an essential trace element in humans
Cleavages of caspase 3 and PARP were observed in NB4 cells, whereas the increase of P62 and the decrease of Beclin-1 and LC3II reflected that selenite exposure inhibited autophagy in NB4 cells (Figure 1a)
We found that survivin-2B regulated apoptosis by mechanisms different from those of wild-type survivin that had been demonstrated previously
Summary
Selenium is an essential trace element in humans. Emerging evidence has demonstrated that a super-nutritional intake of selenite can inhibit tumor cell growth. Our previous study showed that the addition of selenite switched cells from undergoing protective autophagy to apoptosis, and the mechanism was through the downregulation of Hsp90.9 In addition, reports using other cell lines have shown that selenite promotes both autophagy and apoptosis.[10,11,12,13] On the basis of these previous studies, elucidating the relationship between autophagy and apoptosis in cancer cells after selenite exposure is necessary. Studies have shown that AML patients have a lower survival rate if higher levels of survivin-2B are observed,[20] whereas in EU-3 cells, an ALL cell line, survivin-2B can have a proapoptotic role.[21] The current study found that selenite downregulated the expression of survivin-2B and switched protective autophagy to apoptosis in NB4 cells. Our investigation revealed the mechanisms by which survivin-2B regulated autophagy and apoptosis in selenite-treated NB4 cells
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