J Biol Chem：方靖等揭示FOXO3a基因在肿瘤中作用研究的新进展

无血清条件下FOXO3a通过BCL10-NFkB途径保护细胞免受凋亡机制模式图

近日，美国生物化学杂志Journal of Biological Chemistry在线发表了中国科学院上海生命科学研究院营养科学研究所方靖研究组的研究论文“Forkhead Transcription Factor FOXO3a Activates NF-kB through B-cell lymphoma/leukemia 10 (BCL10) and Promotes Tumor Cell Survival in Serum-deprivation”。该研究揭示了抑癌基因FOXO3a (Forkhead box O3) 在肿瘤发生发展中新的功能和机制。

FOXO3a是转录因子FOX蛋白家族中重要一员，与细胞转化、肿瘤发生发展有密切关系，被认为是肿瘤抑制基因。近来，也有研究显示FOXO3a具有保护肿瘤细胞免受氧化应激和低氧不利条件的影响。这些研究结果表明FOXO3a在不同条件与环境下可能发挥不同的作用。

方靖研究员指导的博士研究生李兆栋和张海生发现在无血清培养条件下，FOXO3a可以促进肿瘤细胞抵抗凋亡。这一结果提示，在生长因子和营养匮乏条件下该蛋白具有保护肿瘤细胞的作用。进一步的分子机制研究表明，无血清条件下激活的FOXO3a启动BCL10基因表达进而激活NF-kB。NF-kB是转录因子，可以引起细胞生长和抗凋亡相关基因的表达。因此，在无血清条件下，FOXO3a可能通过BCL10-NFkB途径保护肿瘤细胞免受凋亡。这些结果结合以前相关报道进一步表明，在不同环境条件下，FOXO3a对肿瘤细胞有可能会起到完全不同的作用。因此，以FOXO3a为靶点进行肿瘤治疗应慎重。

该研究受到国家自然科学基金委、科技部和中国科学院的支持。

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.