Neurofilament heavy polypeptide regulates the Akt-β-catenin pathway in human esophageal squamous cell carcinoma

Myoung Sook Kim, Xiaofei Chang, Cynthia LeBron, Jatin K. Nagpal, Juna Lee, Yiping Huang, Keishi Yamashita, Barry Trink, Edward A. Ratovitski, David Sidransky

Research output: Contribution to journalArticle

Abstract

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/β-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 β-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/bβ-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.

Original languageEnglish (US)
Article numbere9003
JournalPLoS One
Volume5
Issue number2
DOIs
StatePublished - Feb 3 2010

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Catenins
Intermediate Filaments
squamous cell carcinoma
polypeptides
Peptides
glycolysis
Glycolysis
Cell growth
pyruvate dehydrogenase (lipoamide)
cell growth
Growth
2-deoxyglucose
Neoplasms
pyruvate kinase
neoplasms
Pyruvate Kinase
Methylation
Deoxyglucose
RNA Interference
Esophageal Squamous Cell Carcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Neurofilament heavy polypeptide regulates the Akt-β-catenin pathway in human esophageal squamous cell carcinoma. / Kim, Myoung Sook; Chang, Xiaofei; LeBron, Cynthia; Nagpal, Jatin K.; Lee, Juna; Huang, Yiping; Yamashita, Keishi; Trink, Barry; Ratovitski, Edward A.; Sidransky, David.

In: PLoS One, Vol. 5, No. 2, e9003, 03.02.2010.

Research output: Contribution to journalArticle

Kim, MS, Chang, X, LeBron, C, Nagpal, JK, Lee, J, Huang, Y, Yamashita, K, Trink, B, Ratovitski, EA & Sidransky, D 2010, 'Neurofilament heavy polypeptide regulates the Akt-β-catenin pathway in human esophageal squamous cell carcinoma', PLoS One, vol. 5, no. 2, e9003. https://doi.org/10.1371/journal.pone.0009003
Kim, Myoung Sook ; Chang, Xiaofei ; LeBron, Cynthia ; Nagpal, Jatin K. ; Lee, Juna ; Huang, Yiping ; Yamashita, Keishi ; Trink, Barry ; Ratovitski, Edward A. ; Sidransky, David. / Neurofilament heavy polypeptide regulates the Akt-β-catenin pathway in human esophageal squamous cell carcinoma. In: PLoS One. 2010 ; Vol. 5, No. 2.
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