Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis

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Xiaojun Zha1, Fang Wang, Ying Wang

  • 1State 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.

Cancer Research
|January 5, 2011
PubMed

Insights

Mammalian target of rapamycin (mTOR) pathway activation drives cancer by upregulating lactate dehydrogenase B (LDHB). Targeting LDHB offers a new therapeutic strategy for mTOR-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) pathway is crucial in cell growth and metabolism.
  • Aberrant activation of the mTOR pathway, often downstream of receptor tyrosine kinases (RTKs), PI3K, and AKT, is implicated in tumorigenesis.
  • The precise mechanisms by which mTOR activation promotes cancer remain incompletely understood.

Purpose of the Study:

  • To investigate the downstream effectors of mTOR signaling in cancer development.
  • To identify novel molecular targets for therapeutic intervention in mTOR-driven cancers.
  • To elucidate the role of lactate dehydrogenase B (LDHB) in mTOR-mediated tumorigenesis.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) with genetic alterations in TSC1, TSC2, PTEN, or AKT1.
  • Examined lactate dehydrogenase B (LDHB) gene expression in relation to mTOR signaling.
  • Investigated the role of signal transducer and activator of transcription 3 (STAT3) in LDHB transactivation.
  • Assessed the impact of LDHB attenuation on tumor growth in vivo using nude mouse models.

Main Results:

  • Lactate dehydrogenase B (LDHB) expression was upregulated in an mTOR-dependent manner in various genetically modified MEFs.
  • Signal transducer and activator of transcription 3 (STAT3) was identified as a key transactivator of LDHB gene expression, functioning downstream of mTOR.
  • Attenuation of LDHB significantly reduced the tumorigenic potential of oncogenic cells in vivo.
  • LDHB acts as a downstream effector of mTOR in both mouse and human cancer cells.

Conclusions:

  • Lactate dehydrogenase B (LDHB) is a critical downstream target of the mTOR pathway.
  • mTOR-mediated upregulation of LDHB contributes significantly to tumorigenesis.
  • LDHB represents a potential therapeutic target for cancers characterized by aberrant RTK-PI3K-AKT-mTOR signaling.

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