PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer.
Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16-48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (P=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.
Cancer Research UK, Growth Factor Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DU, UK.
S M
SM
Wigfield
S C
SC
Winter
A
A
Giatromanolaki
J
J
Taylor
M L
ML
Koukourakis
A L
AL
Harris
D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference
D017931:DNA Primers; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases