近日,，美國生物化學(xué)雜志Journal of Biological Chemistry在線發(fā)表了中國科學(xué)院上海生命科學(xué)研究院營養(yǎng)科學(xué)研究所方靖研究組的研究論文“Forkhead Transcription Factor FOXO3a Activates NF-kB through B-cell lymphoma/leukemia 10 (BCL10) and Promotes Tumor Cell Survival in Serum-deprivation”。該研究揭示了抑癌基因FOXO3a (Forkhead box O3) 在腫瘤發(fā)生發(fā)展中新的功能和機制。
FOXO3a是轉(zhuǎn)錄因子FOX蛋白家族中重要一員,，與細胞轉(zhuǎn)化、腫瘤發(fā)生發(fā)展有密切關(guān)系,，被認為是腫瘤抑制基因,。近來，也有研究顯示FOXO3a具有保護腫瘤細胞免受氧化應(yīng)激和低氧不利條件的影響,。這些研究結(jié)果表明FOXO3a在不同條件與環(huán)境下可能發(fā)揮不同的作用,。
方靖研究員指導(dǎo)的博士研究生李兆棟和張海生發(fā)現(xiàn)在無血清培養(yǎng)條件下，F(xiàn)OXO3a可以促進腫瘤細胞抵抗凋亡,。這一結(jié)果提示,，在生長因子和營養(yǎng)匱乏條件下該蛋白具有保護腫瘤細胞的作用。進一步的分子機制研究表明,，無血清條件下激活的FOXO3a啟動BCL10基因表達進而激活NF-kB,。NF-kB是轉(zhuǎn)錄因子，可以引起細胞生長和抗凋亡相關(guān)基因的表達,。因此,，在無血清條件下，F(xiàn)OXO3a可能通過BCL10-NFkB途徑保護腫瘤細胞免受凋亡,。這些結(jié)果結(jié)合以前相關(guān)報道進一步表明,，在不同環(huán)境條件下，F(xiàn)OXO3a對腫瘤細胞有可能會起到完全不同的作用,。因此,，以FOXO3a為靶點進行腫瘤治療應(yīng)慎重。
該研究受到國家自然科學(xué)基金委,、科技部和中國科學(xué)院的支持,。（生物谷Bioon.com）
doi:10.1074/jbc.M111.291708
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Forkhead transcription factor FOXO3a activates NF-kB through B-cell lymphoma/leukemia (BCL10) and promotes tumor cell survival in serum-deprivation
Zhaodong Li, Haisheng Zhang, Ying Chen, Li Fan and Jing Fang*
FOXO3a, a member of Forkhead box O (FoxO) transcription factor family, is believed a tumor suppressor because it was found that FOXO3a inactivation promoted cell transformation and tumor progression. There are also a few studies showing that FOXO3a protected cells under stress conditions including oxidative stress, serum-deprivation, and hypoxia. It was reported that FOXO3a promoted invasion of cancer cells. Thus, the role of FOXO3a in cancer is complicated. Here, we report that FOXO3a is a positive regulator of nuclear factor kB (NF-kB) signaling. We found that overexpression of FOXO3a increased and knockdown of FOXO3a repressed NF-kB activities. Mechanistic studies indicate that FOXO3a activated NF-kB via inducing expression of B-cell lymphoma/leukemia 10 (BCL10), an upstream regulator of IkB kinase (IKK)/NF-kB signaling. We found that the serum-deprivation activated NF-kB, which was blocked by inhibition of FOXO3a. And knockdown of FOXO3a enhanced cell apoptosis under serum-free condition, which was inhibited by overexpression of BCL10. These results suggest that FOXO3a promotes cell survival via BCL10/NF-kB in serum-starvation. Our findings may add additional layer to the complexity of the role of FOXO3a in cancer. Therefore, caution might be taken when FOXO3a is employed as a target for cancer therapy.
