Role of neutral ceramidase in colon cancer

Mónica García-Barros, Nicolas Coant, Toshihiko Kawamori, Masayuki Wada, Ashley J. Snider, Jean Philip Truman, Bill X. Wu, Hideki Furuya, Christopher J. Clarke, Agnieszka B. Bialkowska, Amr Ghaleb, Vincent W. Yang, Lina M. Obeid, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resultedinloss of β-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected fromtumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and thesedata suggest that this enzyme is a suitable and novel target for colon cancer therapy.

Original languageEnglish (US)
Pages (from-to)4159-4171
Number of pages13
JournalFASEB Journal
Volume30
Issue number12
DOIs
StatePublished - Dec 2016
Externally publishedYes

Keywords

  • Aberrant crypt foci
  • Apoptosis
  • Azoxymethane
  • Sphingolipids ceramide

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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