Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells.
Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 activation. The gender specificity of LAM suggests that estradiol contributes to disease development, yet the underlying pathogenic mechanisms are not completely understood. Using metabolomic profiling, we identified an estradiol-enhanced pentose phosphate pathway signature in Tsc2-deficient cells. Estradiol increased levels of cellular NADPH, decreased levels of reactive oxygen species, and enhanced cell survival under oxidative stress. Mechanistically, estradiol reactivated Akt in TSC2-deficient cells in vitro and in vivo, induced membrane translocation of glucose transporters (GLUT1 or GLUT4), and increased glucose uptake in an Akt-dependent manner. (18)F-FDG-PET imaging demonstrated enhanced glucose uptake in xenograft tumors of Tsc2-deficient cells from estradiol-treated mice. Expression array study identified estradiol-enhanced transcript levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. Consistent with this, G6PD was abundant in xenograft tumors and lung metastatic lesions of Tsc2-deficient cells from estradiol-treated mice. Molecular depletion of G6PD attenuated estradiol-enhanced survival in vitro, and treatment with 6-aminonicotinamide, a competitive inhibitor of G6PD, reduced lung colonization of Tsc2-deficient cells. Collectively, these data indicate that estradiol promotes glucose metabolism in mTORC1 hyperactive cells through the pentose phosphate pathway via Akt reactivation and G6PD upregulation, thereby enhancing cell survival under oxidative stress. Interestingly, a strong correlation between estrogen exposure and G6PD was also found in breast cancer cells. Targeting the pentose phosphate pathway may have therapeutic benefit for LAM and possibly other hormonally dependent neoplasms.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
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Y
Sun
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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X
Gu
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
E
E
Zhang
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
M-A
MA
Park
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
A M
AM
Pereira
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
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S
Wang
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
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T
Morrison
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
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C
Li
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
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J
Blenis
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
V H
VH
Gerbaudo
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
E P
EP
Henske
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Blackfan Circle, 6th Floor, Boston, MA 02115, USA.
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Yu
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004343:Drug Implants; D004789:Enzyme Activation; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D055432:Metabolomics; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
D004343:Drug Implants; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C495677:SLC2A1 protein, human; C495680:SLC2A2 protein, human; C495679:Slc2a1 protein, rat; C495683:Slc2a2 protein, rat; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D009249:NADP; D005954:Glucosephosphate Dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose