title: 4EBP1/c-MYC/PUMA and NF-κB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells.
abstract: The mammalian target of rapamycin (mTOR), a kinase that regulates proliferation and apoptosis, has been extensively evaluated as a therapeutic target in multiple malignancies. Rapamycin analogs, which partially inhibit mTOR complex 1 (mTORC1), exhibit immunosuppressive and limited antitumor activity, but sometimes activate survival pathways through feedback mechanisms involving mTORC2. Thus, attention has turned to agents targeting both mTOR complexes by binding the mTOR active site. Here we show that disruption of either mTOR-containing complex is toxic to acute lymphocytic leukemia (ALL) cells and identify 2 previously unrecognized pathways leading to this cell death. Inhibition of mTORC1-mediated 4EBP1 phosphorylation leads to decreased expression of c-MYC and subsequent upregulation of the proapoptotic BCL2 family member PUMA, whereas inhibition of mTORC2 results in nuclear factor-κB-mediated expression of the Early Growth Response 1 (EGR1) gene, which encodes a transcription factor that binds and transactivates the proapoptotic BCL2L11 locus encoding BIM. Importantly, 1 or both pathways contribute to death of malignant lymphoid cells after treatment with dual mTORC1/mTORC2 inhibitors. Collectively, these observations not only provide new insight into the survival roles of mTOR in lymphoid malignancies, but also identify alterations that potentially modulate the action of mTOR dual inhibitors in ALL.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Seongseok
authors.initials: S
authors.lastname: Yun
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Vincelette
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Katherine L B
authors.initials: KL
authors.lastname: Knorr
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; and.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; and.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; and.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD; and.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN;
authors.forename: Andrea E Wahner
authors.initials: AE
authors.lastname: Hendrickson
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Department of Oncology, Mayo Clinic, Rochester, MN; Department of Medicine and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Department of Oncology, Mayo Clinic, Rochester, MN; Department of Medicine and.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; C497325:EGR1 protein, human; C087000:EIF4EBP1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; C489427:MYC protein, human; D046912:Multiprotein Complexes; D016328:NF-kappa B; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases