title: The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B.
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.
authors.affiliation: Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tambe
authors.affiliation: Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.|Department of Cell Biology and Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hasebe
authors.affiliation: Department of Urology, Kohka Public Hospital, Kohka, Shiga, Japan.
authors.forename: Chul Jang
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga, Japan.
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D005260:Female; D055786:Gene Knockout Techniques; D016147:Genes, Tumor Suppressor; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; C486298:Srpx protein, mouse; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1; D005947:Glucose
keywords: Warburg effect; drs; knockout mouse; lactate dehydrogenase