Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.
Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/beta-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of beta-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.
Head and Neck Cancer Research Division, Department of Otolaryngology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Myoung Sook
MS
Kim
Xiaofei
X
Chang
Cynthia
C
LeBron
Jatin K
JK
Nagpal
Juna
J
Lee
Yiping
Y
Huang
Keishi
K
Yamashita
Barry
B
Trink
Edward A
EA
Ratovitski
David
D
Sidransky
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D003847:Deoxyglucose / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D015870:Gene Expression; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000096926:Benzenesulfonamides
D002747:Chlorpropamide; D003847:Deoxyglucose; D016900:Neurofilament Proteins; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C111224:API 2; D000096926:Benzenesulfonamides; C051774:neurofilament protein H