Data from Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis

Abstract

<div>Abstract<p>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 <i>TSC1<sup>−/−</sup></i>, <i>TSC2<sup>−/−</sup></i>, <i>PTEN<sup>−/−</sup></i>, or activated AKT1-expressing mouse embryonic fibroblasts (MEF). <i>LDHB</i> 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. <i>Cancer Res; 71(1); 13–8. ©2011 AACR</i>.</p></div>