Premium
The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase‐B
Author(s) -
Tambe Yukihiro,
Hasebe Masahiro,
Kim Chul Jang,
Yamamoto Akitsugu,
Inoue Hirokazu
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22258
Subject(s) - downregulation and upregulation , biology , lactate dehydrogenase , glycolysis , warburg effect , lactate dehydrogenase a , cancer cell , cell culture , microbiology and biotechnology , anaerobic glycolysis , cancer research , cancer , metabolism , biochemistry , enzyme , gene , genetics
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. © 2015 Wiley Periodicals, Inc.