Estrogen activates pyruvate kinase M2 and increases the growth of TSC2-deficient cells

PLoS One. 2020 Feb 20;15(2):e0228894. doi: 10.1371/journal.pone.0228894. eCollection 2020.


Lymphangioleiomyomatosis (LAM) is a devastating lung disease caused by inactivating gene mutations in either TSC1 or TSC2 that result in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). As LAM occurs predominantly in women during their reproductive age and is exacerbated by pregnancy, the female hormonal environment, and in particular estrogen, is implicated in LAM pathogenesis and progression. However, detailed underlying molecular mechanisms are not well understood. In this study, utilizing human pulmonary LAM specimens and cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we tested the hypothesis that estrogen promotes the growth of mTORC1-hyperactive cells through pyruvate kinase M2 (PKM2). Estrogen increased the phosphorylation of PKM2 at Ser37 and induced the nuclear translocation of phospho-PKM2. The estrogen receptor antagonist Faslodex reversed these effects. Restoration of TSC2 inhibited the phosphorylation of PKM2 in an mTORC1 inhibitor-insensitive manner. Finally, accumulation of phosphorylated PKM2 was evident in pulmonary nodule from LAM patients. Together, our data suggest that female predominance of LAM might be at least in part attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. Targeting metabolic regulators of PKM2 might have therapeutic benefits for women with LAM and other female-specific neoplasms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Estrogens / metabolism*
  • Estrogens / physiology
  • Female
  • Humans
  • Lung / pathology
  • Lung Neoplasms / pathology
  • Lymphangioleiomyomatosis / genetics
  • Lymphangioleiomyomatosis / physiopathology
  • Mechanistic Target of Rapamycin Complex 1
  • Phosphorylation
  • Pyruvate Kinase / metabolism*
  • Pyruvate Kinase / physiology
  • Rats
  • Signal Transduction / drug effects
  • Tuberous Sclerosis Complex 1 Protein / genetics
  • Tuberous Sclerosis Complex 1 Protein / metabolism
  • Tuberous Sclerosis Complex 2 Protein / genetics*
  • Tuberous Sclerosis Complex 2 Protein / metabolism
  • Tumor Suppressor Proteins / genetics


  • Estrogens
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Pyruvate Kinase
  • Mechanistic Target of Rapamycin Complex 1