title: Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis.
abstract: Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearingTSC2mutations migrate to the lungs, proliferate, and cause cystic remodeling. The female predominance indicates that estrogen plays a critical role in LAM pathogenesis, and we have proposed that estrogen promotes LAM cell metastasis by inhibition of anoikis. We report here that estrogen increased LAM patient-derived cells' resistance to anoikis in vitro, accompanied by decreased accumulation of the proapoptotic protein Bim, an activator of anoikis. The resistance to anoikis was reversed by the proteasome inhibitor, bortezomib. Treatment of LAM patient-derived cells with estrogen plus bortezomib promoted anoikis compared with estrogen alone. Depletion of Bim by siRNA in TSC2-deficient cells resulted in anoikis resistance. Treatment of mice with bortezomib reduced estrogen-promoted lung colonization of TSC2-deficient cells. Importantly, molecular depletion of Bim by siRNA in Tsc2-deficient cells increased lung colonization in a mouse model. Collectively, these data indicate that Bim plays a key role in estrogen-enhanced survival of LAM patient-derived cells under detached conditions that occur with dissemination. Thus, targeting Bim may be a plausible future treatment strategy in patients with LAM.
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.|The First Affiliated Hospital of Zhengzhou University, Department of Oncology, Zhengzhou, Henan, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Erik Y
authors.initials: EY
authors.lastname: Zhang
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Harvard Medical School, Department of Cell Biology, Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Sun
authors.affiliation: Boston University School of Medicine, Department Molecular and Translational Medicine, Boston, Massachusetts, USA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Morrison
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.|The First Affiliated Hospital of Zhengzhou University, Department of Oncology, Zhengzhou, Henan, China.
authors.forename: Xiangke
authors.initials: X
authors.lastname: Li
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.|The First Affiliated Hospital of Guangzhou Medical University, Department of Gastrointestinal Surgery, Guangzhou, China.
authors.forename: Yuanguang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: University of Cincinnati College of Medicine, Department of Pathology and Lab Medicine, Cincinnati, OH, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, Cincinnati, Ohio, USA.
authors.forename: Nagla A
authors.initials: NA
authors.lastname: Karim
authors.affiliation: The First Affiliated Hospital of Zhengzhou University, Biotherapy Center and Department of Oncology, Zhengzhou, Henan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Harvard Medical School, Department of Cell Biology, Boston, Massachusetts, USA.|Weill Cornell Medicine Sandra and Edward Meyer Cancer Center, New York, New York, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.affiliation: Drexel University College of Medicine, Department of Biochemistry and Molecular Biology, Philadelphia, Pennsylvania, USA.
authors.forename: Mauricio J
authors.initials: MJ
authors.lastname: Reginato
authors.affiliation: Brigham and Women's Hospital-Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.affiliation: University of Cincinnati College of Medicine, Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, Cincinnati, Ohio, USA.|The First Affiliated Hospital of Zhengzhou University, Department of Oncology, Zhengzhou, Henan, China.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
mesh_terms: D000818:Animals; D023102:Anoikis; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D000069286:Bortezomib / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology; D008171:Lung Diseases / Q000473:pathology*; D018192:Lymphangioleiomyomatosis / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000072224:Bcl-2-Like Protein 11; D004967:Estrogens; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib