The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B

Mol Carcinog. 2016 Jan;55(1):52-63. doi: 10.1002/mc.22258. Epub 2015 Jan 24.

Abstract

Previously, we showed that drs contributes to suppression of malignant tumor formation in drs-knockout (KO) mice. In this study, we demonstrate the regulation of glucose metabolism by drs using comparisons of drs-KO and wild-type (WT) mouse embryonic fibroblasts (MEFs). Extracellular acidification, lactate concentration, and glucose consumption in drs-KO cells were significantly greater than those in WT cells. Metabolomic analyses also confirmed enhanced glycolysis in drs-KO cells. Among glycolysis-regulating proteins, expression of lactate dehydrogenase (LDH)-B was upregulated at the post-transcriptional level in drs-KO cells and increased LDH-B expression, LDH activity, and acidification of culture medium in drs-KO cells were suppressed by retroviral rescue of drs, indicating that LDH-B plays a critical role for glycolysis regulation mediated by drs. In WT cells transformed by activated K-ras, expression of endogenous drs mRNA was markedly suppressed and LDH-B expression was increased. In human cancer cell lines with low drs expression, LDH-B expression was increased. Database analyses also showed the correlation between downregulation of drs and upregulation of LDH-B in human colorectal cancer and lung adenocarcinoma tissues. Furthermore, an LDH inhibitor suppressed anchorage-independent growth of human cancer cells and MEF cells transformed by activated K-ras. These results indicate that drs regulates glucose metabolism via LDH-B. Downregulating drs may contribute to the Warburg effect, which is closely associated with malignant progression of cancer cells.

Keywords: Warburg effect; drs; knockout mouse; lactate dehydrogenase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cluster Analysis
  • Female
  • Gene Knockout Techniques
  • Genes, Tumor Suppressor*
  • Glucose / metabolism*
  • Humans
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / metabolism*
  • Male
  • Membrane Proteins / genetics*
  • Metabolome
  • Metabolomics / methods
  • Mice
  • Mice, Knockout
  • Neoplasms / genetics
  • Neoplasms / metabolism

Substances

  • Isoenzymes
  • Membrane Proteins
  • Srpx protein, mouse
  • L-Lactate Dehydrogenase
  • lactate dehydrogenase 1
  • Glucose