title: Forkhead transcription factor FOXO3a protein activates nuclear factor κB through B-cell lymphoma/leukemia 10 (BCL10) protein and promotes tumor cell survival in serum deprivation.
abstract: FOXO3a, a member of the Forkhead box O (FoxO) transcription factor family, is believed to be 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 κB (NF-κB) signaling. We found that overexpression of FOXO3a increased and knockdown of FOXO3a repressed NF-κB activities. Mechanistic studies indicate that FOXO3a activated NF-κB via inducing expression of B-cell lymphoma/leukemia 10 (BCL10), an upstream regulator of IκB kinase (IKK)/NF-κB signaling. We found that the serum deprivation activated NF-κB, which was blocked by inhibition of FOXO3a. Knockdown of FOXO3a enhanced cell apoptosis under serum-free conditions, which was inhibited by overexpression of BCL10. These results suggest that FOXO3a promotes cell survival via BCL10/NF-κB in serum starvation. Our findings may add another layer to the complexity of the role of FOXO3a in cancer. Therefore, caution should be taken when FOXO3a is employed as a target for cancer therapy.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jfang@sibs.ac.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002470:Cell Survival; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D051550:I-kappa B Kinase