title: The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress.
abstract: Normal cells possess adaptive mechanisms to couple energy availability with cell growth (cell size increase) and survival, and imbalances are associated with major diseases such as cancer. Inactivation of critical regulators involved in energy stress response, including adenosine monophosphate-activated protein kinase (AMPK), liver kinase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased apoptosis under energy stress. These energy stress regulators are also important in tumor suppression and metabolism. Here, we show that forkhead box O (FoxO) transcription factor, a central regulator of tumor suppression and metabolism, plays a unique role in energy stress response. FoxOs inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of FoxOs alleviates energy stress-mediated mTORC1 repression. Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit decreased apoptosis under energy stress. FoxOs operate to inhibit mTORC1 signaling and cell survival independent of AMPK and TSC. Integrated transcriptomic and functional analyses identified BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-a negative regulator of both Rheb and Bcl2 prosurvival family members-as a key downstream target of FoxOs to inhibit mTORC1 function and promote apoptosis in response to energy stress. We show that p38β, but not AMPK, is likely to function upstream of FoxO-BNIP3 to mediate energy stress response. Finally, we reveal that low expression of FoxO or BNIP3 correlates with poor clinical outcomes in renal cancer patients. Together, our study uncovers a novel signaling circuit functioning to mediate cellular energy responses to control cell growth and survival. These findings also have important implications to human cancers.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: 1] Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Program of Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007680:Kidney Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013312:Stress, Physiological; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C508686:BNip3 protein, mouse; D014408:Biomarkers, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases