Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

Thomas Mcfate,Ahmed Mohyeldin,Huasheng Lu,Jay Thakar,Jeremy Henriques,Nader D Halim,Hong Wu,Michael J Schell,Tsz Mon Tsang,Orla Teahan,Shaoyu Zhou,Joseph A Califano,Nam Ho Jeoung,Robert A Harris,Ajay Verma

doi:10.1074/jbc.m801765200

Abstract

High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha (PDHalpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHalpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.

Highlights

Cancer is a disease whereby genetic mutation results in uncontrolled cell growth combined with malignancy
Normoxic or basal hypoxia-inducible transcription factor-1 (HIF-1)␣ expression can be mediated by products of glucose metabolism and is additive with hypoxiainduced HIF-1␣ accumulation [9]
22B cells displayed the highest induction of HIF-1␣ following 4-h exposures to hypoxia (1% O2) (Fig. 1D)

Summary

Introduction

Cancer is a disease whereby genetic mutation results in uncontrolled cell growth combined with malignancy. This approach confirmed a rylation dose-dependently in 22A cells but was surprisingly pronounced reduction in cellular lactate following PDK-1 without significant effect in 22B cells, even at concentrations up knockdown but few other changes in metabolite accumulation to 20 mM (Fig. 1, F and G).

Results

Conclusion