Targeting Lactate Dehydrogenase A Research Articles

Abstract C15: Combinatorial regulation of neuroblastoma tumor progression by HIF1α and N-myc transcriptional factors

Abstract Deregulation of Myc and activation of hypoxia inducible factors (HIFs) frequently occur in solid tumors. In human neuroblastoma, amplification of the N-MYC gene predicts poor prognosis and resistance to therapy. Interestingly, we demonstrated here that HIF1α, but not HIF2α, is preferentially expressed in both N-MYC amplified neuroblastoma cells and primary tumors in comparison to non-amplified ones. Expression of HIF2α in N-MYC amplified cells appears to be silenced largely through DNA methylation and histone deacetylation. Interplay between N-Myc and HIF1α plays critical roles in progression of neuroblastomas. On one hand, N-Myc overrides the inhibitory function of HIF1α on cell cycle progression under hypoxia, which frequently occurs in solid tumors and is well known to inhibit cell growth. Of note, proliferation of N-MYC amplified cells is largely unaltered under hypoxia. On the other hand, HIF1α, together with N-Myc, cooperates to regulate aerobic glycolysis (the Warburg effect) of neuroblastoma. The near-universal glycolytic switch of N-MYC amplified neuroblastoma cells may be an essential tumor trait and a consequence of the cellular adaptation to intermittent hypoxia. Targeting either HIF1α or N-Myc significantly decreases expression of genes involved in glycolysis, such as lactate dehydrogenase A (LDHA), and inhibits cell proliferation in vitro under normoxia. Strikingly, N-MYC amplified cells are addicted to LDHA expression. Reduction in LDHA activity completely inhibits their proliferation under both normoxia and hypoxia. Taken together, our results demonstrate that neuroblastoma cells differentially respond to hypoxia with distinct HIFα induction patterns, and suggest the HIF1α/N-Myc axis may represent a pharmacologically tractable pathway for the potential treatment of N-MYC amplified neuroblastomas. In particular, we propose targeting LDHA may be a promising and nontoxic approach in treatment of N-MYC amplified neuroblastomas, given that depletion of LDHA expression completely inhibits growth of N-MYC amplified cells and individuals deficient in LDHA expression show no obvious symptoms under normal conditions. Citation Information: Cancer Res 2009;69(23 Suppl):C15.