title: Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis.
abstract: Mammalian target of rapamycin (mTOR) is a major downstream effector of the receptor tyrosine kinase (RTK)-phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homologue 1 (AKT) signaling pathway. Although this signaling network is frequently altered in cancer, the underlying mechanisms that cause tumorigenesis as a result of activated mTOR remain largely unknown. We report here that expression of lactate dehydrogenase B (LDHB), a critical enzymatic activator of glycolysis, was upregulated in an mTOR-dependent manner in TSC1(-/-), TSC2(-/-), PTEN(-/-), or activated AKT1-expressing mouse embryonic fibroblasts (MEF). LDHB gene expression was transactivated by signal transducer and activator of transcription 3 (STAT3), a key tumorigenic driver in many cancers, acting as a downstream mTOR effector in both mouse MEFs and human cancer cells. LDHB attenuation blunted the tumorigenic potential of oncogenic TSC2-null cells in nude mice. We concluded that LDHB is a downstream target of mTOR that is critical for oncogenic mTOR-mediated tumorigenesis. Our findings offer proof of concept for targeting LDHB as a therapeutic strategy in cancers driven by aberrant activation of the RTK-PI3K-AKT-mTOR signaling cascade.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Shaozong
authors.initials: S
authors.lastname: He
authors.forename: Yanling
authors.initials: Y
authors.lastname: Jing
authors.forename: Xueyan
authors.initials: X
authors.lastname: Wu
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D050796:STAT3 Transcription Factor; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1; D058570:TOR Serine-Threonine Kinases