The activation of lactate dehydrogenase induced by mTOR drives neoplastic change in breast epithelial cells

PLoS One. 2018 Aug 23;13(8):e0202588. doi: 10.1371/journal.pone.0202588. eCollection 2018.

Abstract

mTOR kinase and the A isoform of lactate dehydrogenase (LDH-A) are key players controlling the metabolic characteristics of cancer cells. By using cultured human breast cells as a "metabolic tumor" model, we attempted to explore the correlation between these two factors. "Metabolic tumors" are defined as neoplastic conditions frequently associated with features of the metabolic syndrome, such as hyper-insulinemia and hyper-glycemia. MCF-7 cells (a well differentiated carcinoma) and MCF-10A cells (a widely used model for studying normal breast cell transformation) were used in this study. These cells were exposed to known factors triggering mTOR activation. In both treated cultures, we evaluated the link between mTOR kinase activity and the level of LDH expression / function. Furthermore, we elaborated the metabolic changes produced in cells by the mTOR-directed LDH-A up-regulation. Interestingly, we observed that in the non-neoplastic MCF-10A culture, mTOR-directed up-regulation of LDH-A was followed by a reprogramming of cell metabolism, which showed an increased dependence on glycolysis rather than on oxidative reactions. As a consequence, lactate production appeared to be enhanced and cells began to display increased self-renewal and clonogenic power: signals suggestive of neoplastic change. Enhanced clonogenicity of cells was abolished by rapamycin treatment, and furthermore heavily reduced by LDH enzymatic inhibition. These results highlighted a mechanistic link between metabolic alterations and tumorigenesis, whereby suggesting LDH inhibition as a possible chemo-preventive measure to target the metabolic alterations driving neoplastic change.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Cell Proliferation / genetics
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Glycolysis / genetics
  • Humans
  • Isoenzymes / genetics
  • L-Lactate Dehydrogenase / genetics*
  • Lactate Dehydrogenase 5
  • MCF-7 Cells
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Phosphorylation
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Isoenzymes
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Grants and funding

This work was supported by the University of Bologna, RFO funds, www.unibo.it (GDS) and by Roberto and Cornelia Pallotti's Legacy for Cancer Research, www.unibo.it (GDS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.